Fused heteroaryls and their uses

ABSTRACT

Provided are certain fused heteroaryls, compositions thereof and methods of use therefor.

Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks) are a family ofenzymes that may be involved in cellular functions such as cell growth,proliferation, differentiation, motility, survival and intracellulartrafficking, which in turn can be involved in cancer.

The PI3K family may include four distinct classes defined by structuraland functional characteristics and termed as Classes I-IV. The mostfully characterized class may be the Class I-PI3Ks. Class I comprisesthree class I α isoforms—PI3Kα, PI3Kβ and PI3Kδ. PI3Kα appears to behighly relevant in human cancers and malignancies. PI3Kα can beoverexpressed in human cancers.

Mammalian target of rapamycin (mTOR) is the downstream kinase of PI3Kfamily. Inhibition of mTOR can inhibit the activity of PI3K. Therefore,the PI3K/mTOR pathway can be exploited for new cancer drug discovery.

Provided is at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt thereof wherein

A¹ is N or CH;

A⁴ and A⁵ are independently N or CR²;

A² and A³, together with B ring are a 5-membered heteroaryl orheterocycle containing 1 to 4 heteroatoms selected from N, O, and S, andsaid 5-membered heteroaryl or heterocycle is optionally substituted byone or more groups independently chosen from alkyl, alkenyl, alkynyl,aryl, cycloalkyl, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl,heteroaryl, and heterocycle;

provided that A² and A³, together with the B ring are not

is a single bond or a double bond;

R¹ is heteroaryl, optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, —OR^(b),—S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, andheterocycle;

R and R² are independently chosen from H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, and heterocycle;

and each of said above alkyl, alkenyl, alkynyl, aryl, cycloalkyl,haloalkyl, heteroaryl and heterocycle can be optionally substituted byone or more groups independently chosen from optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are eachindependently chosen from H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle,

or R^(a) and R^(c), and/or R^(c) and R^(d), and/or R^(c) and R^(e),and/or R^(c) and R^(f), and/or R^(d) and R^(e), and/or R^(g) and R^(f)together with the atom(s) to which they are attached, form a 3-10membered optionally substituted heterocycle ring; and

for each occurrence, n is independently 0, 1, or 2;

wherein each optionally substituted group above can be unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, cycloalkyl, oxo,aryl, heterocycle, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halo, —OH,—NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano,nitro, oxo, —OC₂H, —C(O)OC₁-C₄ alkyl, —C(O)Ocycloalkyl, —C(O)Oaryl,—C(O)Oheteroaryl, —C(O)Oheterocycle, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONR′R″ wherein R′ and R″ with the N to which they are attached form aheterocycle, —CON(cycloalkyl)(cycloalkyl),—CON(heterocycle)(heterocycle), —CONH(C₁-C₄ alkyl), —CONH(cycloalkyl),—CONH(heterocycle), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(cycloalkyl),—NHC(O)(heterocycle), —NHC(O)(aryl) such as —NHC(O)(phenyl),—NHC(O)(heteroaryl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(cycloalkyl), —N(C₁-C₄ alkyl)C(O)(heterocycle), —N(C₁-C₄alkyl)C(O)(aryl) such as —N(C₁-C₄ alkyl)C(O)(phenyl), N(C₁-C₄alkyl)C(O)(heteroaryl), —C(O)C₁-C₄ alkyl, —C(O)(cycloalkyl),—C(O)(heterocycle), —C(O)(aryl) such as —C(O) phenyl, —C(O)(heteroaryl),—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)(cycloalkyl),—C(O)(heterocycle), —OC(O)(heteroaryl), OC(O)(aryl), such as—OC(O)phenyl, —SO₂(C₁-C₄ alkyl), —SO₂(cycloalkyl), —SO₂(heterocycle),—SO₂(aryl) such as SO₂(phenyl), —SO₂(heteroaryl), —SO₂(C₁-C₄ haloalkyl),—SO₂NH₂, —SO₂NR′R″ wherein R′ and R″ with the N to which they areattached form a heterocycle, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(cycloalkyl),—SO₂NH(heterocycle), —SO₂NH(aryl) such as —SO₂NH(phenyl),—SO₂NH(heteroaryl), —NHSO₂(C₁-C₄ alkyl), NHSO₂(cycloalkyl),NHSO₂(heterocycle), NHSO₂(aryl) such as —NHSO₂(phenyl),NHSO₂(heteroaryl), and —NHSO₂(C₁-C₄ haloalkyl), in which each of alkyl,phenyl, aryl, cycloalkyl, heterocycle, and heteroaryl is optionallysubstituted by one or more groups independently chosen from —OH, halo,cycloalkyl, heterocycle, C₁-C₄ alkyl, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl,C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, cyano,nitro, —NH₂, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), and —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl).

Also provided is a pharmaceutical composition comprising at least onecompound and/or at least one pharmaceutically acceptable salt thereofdescribed herein and at least one pharmaceutically acceptable carrier.

Also provided is a method of inhibiting the activity of PI3K and/or mTORcomprising contacting the enzyme with an effective amount of at leastone compound and/or at least one pharmaceutically acceptable saltthereof described herein.

Also provided is a method of treating cancer responsive to inhibition ofPI3K and/or mTOR comprising administering to a subject in need oftreating for said cancer an effective amount of at least one compoundand/or at least one pharmaceutically acceptable salt thereof describedherein.

Also provided is a use of at lease one compound and/or at least onepharmaceutically acceptable salt thereof described herein in themanufacture of a medicament for inhibiting the activity of PI3K and/ormTOR.

Also provided is a use of at lease one compound and/or at least onepharmaceutically acceptable salt thereof described herein in themanufacture of a medicament for treating cancer.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “alkyl” herein refers to a straight or branched hydrocarbon,containing 1-18, such as 1-12, further such as 1-6 carbon atoms.Examples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. “Lower alkyl” refersto a straight or branched hydrocarbon, containing 1-6, such as 1-4carbon atoms.

The term “alkoxy” herein refers to a straight or branched alkyl group ofthe indicated number of carbon atoms attached through an oxygen bridgesuch as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groupswill usually have from 1 to 6 carbon atoms attached through the oxygenbridge. “Lower alkoxy” refers to a straight or branched alkoxy, whereinthe alkyl portion contains 1-4 carbon atoms.

The term “alkenyl” herein refers to a straight or branched hydrocarbon,containing one or more C═C double bonds and 2-10, such as 2-6 carbonatoms. Examples of alkenyl groups include, but are not limited to,vinyl, 2-propenyl, and 2-butenyl.

The term “alkynyl” herein refers to a straight or branched hydrocarbon,containing one or more C≡O triple bonds and 2-10, such as 2-6 carbonatoms. Examples of alkynyl groups include, but are not limited to,ethynyl, 2-propynyl, and 2-butynyl.

The term “cycloalkyl” refers to saturated and partially unsaturatedcyclic hydrocarbon groups having 3 to 12, such as 3 to 8 carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cyclooctyl. The ring may be saturated orhave one or more double bonds (i.e. partially unsaturated), but notfully conjugated, and not aromatic, as defined herein.

“Aryl” encompasses:

5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

bicyclic ring systems wherein at least one ring is carbocyclic andaromatic, for example, naphthalene, indane, and1,2,3,4-tetrahydroquinoline; and

tricyclic ring systems wherein at least one ring is carbocyclic andaromatic, for example, fluorene.

For example, aryl includes 5 and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered cycloalkyl or heterocyclic ring containingzero or more heteroatoms selected from N, O, and S, provided that thepoint of attachment is at the carbocyclic aromatic ring when thecarbocyclic aromatic ring is fused with a heterocyclic ring, and thepoint of attachment can be at the carbocyclic aromatic ring or at thecycloalkyl when the carbocyclic aromatic ring fused with a cycloalkyl.Bivalent radicals formed from substituted benzene derivatives and havingthe free valences at ring atoms are named as substituted phenyleneradicals. Bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.Aryl, however, does not encompass or overlap in any way with heteroaryl,separately defined below. Hence, if one or more carbocyclic aromaticrings are fused with a heterocyclic aromatic ring, the resulting ringsystem is heteroaryl, not aryl, as defined herein.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

The term “heteroaryl” refers to

5- to 7-membered aromatic, monocyclic rings containing one or more, forexample, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatomsselected from N, O, and S, with the remaining ring atoms being carbon;

8- to 12-membered bicyclic rings containing one or more, for example,from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selectedfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one ring is aromatic and at least one heteroatom is present inthe aromatic ring; and

11- to 14-membered tricyclic rings containing one or more, for example,from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selectedfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one ring is aromatic and at least one heteroatom is present inan aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocyclicaromatic ring fused to a 5- to 7-membered cycloalkyl ring. For suchfused, bicyclic heteroaryl ring systems wherein only one of the ringscontains one or more heteroatoms, the point of attachment may be at theheteroaromatic ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include, but are not limited to, (asnumbered from the linkage position assigned priority 1), pyridyl (suchas 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl,benzoimidazolyl, indolyl, indolinyl, pyridizinyl, triazolyl, quinolinyl,pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl),pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl(such as benzo[d]oxazol-6-yl), benzothiazolyl (such asbenzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and5,6,7,8-tetrahydroisoquinoline.

Bivalent radicals derived from univalent heteroaryl radicals whose namesend in “-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a pyridyl group with two points of attachmentis a pyridylidene. Heteroaryl does not encompass or overlap with aryl asdefined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

By “heterocycle” or “heterocyclic ring” is meant a 4- to 12-memberedmonocyclic, bicyclic or tricyclic saturated or partially unsaturatedring containing at least 2 carbon atoms in addition to 1-3 heteroatomsindependently selected from oxygen, sulfur, and nitrogen. “Heterocycle”also refers to 5- to 7-membered heterocyclic ring containing one or moreheteroatoms selected from N, O, and S fused with 5-, 6-, and/or7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring,provided that the point of attachment is at the heterocyclic ring whenthe heterocyclice ring is fused with a carbocyclic aromatic or aheteroaromatic ring, and that the point of attachment can be at thecycloalkyl or heterocyclic ring when the heterocylic ring is fused withcycloalkyl. “Heterocycle” also refers to an aliphatic spirocyclic ringcontaining one or more heteroatoms selected from N, O, and S, providedthat the point of attachment is at the heterocyclic ring. The rings maybe saturated or have one or more double bonds (i.e. partiallyunsaturated). The heterocycle can be substituted by oxo. The point ofthe attachment may be carbon or heteroatom in the heterocyclic ring. Aheterocyle is not a heteroaryl as defined herein.

Suitable heterocycles include, for example (as numbered from the linkageposition assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyland 3-morpholinyl. Substituted heterocycle also includes ring systemssubstituted with one or more oxo moieties, such as piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom or group is replaced with aselection from the indicated group, provided that the designated atom'snormal valence is not exceeded. When a substituent is oxo (i.e., ═O)then 2 hydrogen atoms on the atom are replaced. Combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds or useful synthetic intermediates. A stablecompound or stable structure is meant to imply a compound that issufficiently robust to survive isolation from a reaction mixture, andsubsequent formulation as an agent having at least practical utility.Unless otherwise specified, substituents are named into the corestructure. For example, it is to be understood that when(cycloalkyl)alkyl is listed as a possible substituent, the point ofattachment of this substituent to the core structure is in the alkylportion.

In some embodiments, “substituted with one or more groups” refers to twohydrogen atoms on the designated atom or group being independentlyreplaced with two selections from the indicated group of substituents.In some embodiments, “substituted with one or more groups” refers tothree hydrogen atoms on the designated atom or group being independentlyreplaced with three selections from the indicated group of substituents.In some embodiments, “substituted with one or more groups” refers tofour hydrogen atoms on the designated atom or group being independentlyreplaced with four selections from the indicated group of substituents.

Compounds described herein include, but are not limited to, whenpossible, their optical isomers, such as enantiomers and diastereomers,mixtures of enantiomers, including racemates, mixtures of diastereomers,and other mixtures thereof, to the extent they can be made by one ofordinary skill in the art by routine experimentation. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates or mixtures of diastereomers. Resolution of theracemates or mixtures of diastereomers, if possible, can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high-pressure liquid chromatography (HPLC)column. In addition, such compounds include Z- and E-forms (or cis- andtrans-forms) of compounds with carbon-carbon double bonds. Wherecompounds described herein exist in various tautomeric forms, the term“compound” is intended to include, to the extent they can be madewithout undue experimentation, all tautomeric forms of the compound.Such compounds also include crystal forms including polymorphs andclathrates, to the extent they can be made by one of ordinary skill inthe art by routine experimentation. Similarly, the term “salt” isintended to include all isomers, racemates, other mixtures, Z- andE-forms, tautomeric forms and crystal forms of the salt of the compound,to the extent they can be made by one of ordinary skill in the artwithout undue experimentation.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, lactate, methanesulfonate,p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate,stearate, alkanoate such as acetate, and salts with HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if a compound described herein is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used without undue experimentation to prepare non-toxicpharmaceutically acceptable addition salts.

A “solvate,” such as a “hydrate,” is formed by the interaction of asolvent and a compound. The term “compound” is intended to includesolvates, including hydrates, of compounds, to the extent they can bemade by one of ordinary skill in the art by routine experimentation.Similarly, “salts” includes solvates, such as hydrates, of salts, to theextent they can be made by one of ordinary skill in the art by routineexperimentation. Suitable solvates are pharmaceutically acceptablesolvates, such as hydrates, including monohydrates and hemi-hydrates, tothe extent they can be made by one of ordinary skill in the art byroutine experimentation.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound.”

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a chemical substance whichhas biological activity. In some embodiments, an “active agent” is achemical substance having pharmaceutical utility.

“Treating,” “treat,” or “treatment” or “alleviation” refers toadministering at least one compound and/or at least one pharmaceuticallyacceptable salt thereof described herein to a subject that has cancer,or has a symptom of cancer, or has a predisposition toward cancer, withthe purpose to cure, heal, alleviate, relieve, alter, remedy,ameliorate, improve, or affect cancer, the symptoms of cancer, or thepredisposition toward cancer.

The term “effective amount” refers to an amount of at least one compoundand/or at least one pharmaceutically acceptable salt thereof describedherein effective to “treat,” as defined above, a disease or disorder ina subject. In the case of cancer, the effective amount may cause any ofthe changes observable or measurable in a subject as described in thedefinition of “treating,” “treat,” “treatment” and “alleviation” above.For example, the effective amount can reduce the number of cancer ortumor cells; reduce the tumor size; inhibit or stop tumor cellinfiltration into peripheral organs including, for example, the spreadof tumor into soft tissue and bone; inhibit and stop tumor metastasis;inhibit and stop tumor growth; relieve to some extent one or more of thesymptoms associated with the cancer, reduce morbidity and mortality;improve quality of life; or a combination of such effects. An effectiveamount may be an amount sufficient to decrease the symptoms of a diseaseresponsive to inhibition of PI3K/mTOR activity. For cancer therapy,efficacy in vivo can, for example, be measured by assessing the durationof survival, time to disease progression (TTP), the response rates (RR),duration of response, and/or quality of life. Effective amounts mayvary, as recognized by those skilled in the art, depending on route ofadministration, excipient usage, and co-usage with other agents.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of PI3K and/or mTORactivity” refers to a decrease in the activity of PI3K and/or mTOR as adirect or indirect response to the presence of at least one compoundand/or at least one pharmaceutically acceptable salt described herein,relative to the activity of PI3K and/or mTOR in the absence of the atleast one compound and/or the at least one pharmaceutically acceptablesalt thereof. The decrease in activity is not bound by theory and may bedue to the direct interaction of the at least one compound and/or atleast one pharmaceutically acceptable salt thereof described herein withPI3K and/or mTOR, or due to the interaction of the at least one compoundand/or at least one pharmaceutically acceptable salt described herein,with one or more other factors that in turn affect PI3K and/or mTORactivity. For example, the presence of at least one compound and/or atleast one pharmaceutically acceptable salt thereof described herein, maydecrease PI3K and/or mTOR activity by directly binding to the PI3Kand/or mTOR, by causing (directly or indirectly) another factor todecrease PI3K and/or mTOR activity, or by (directly or indirectly)decreasing the amount of PI3K and/or mTOR present in the cell ororganism.

The details of one or more embodiments of the invention are set forthbelow.

Provided herein is at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt thereof wherein

A¹ is N or CH;

A⁴ and A⁵ are independently N or CR²;

A² and A³, together with B ring, are a 5-membered heteroaryl orheterocycle containing 1 to 4 heteroatoms selected from N, O, and S, andsaid 5-membered heteroaryl or heterocycle is optionally substituted byone or more groups independently chosen from alkyl, alkenyl, alkynyl,aryl, cycloalkyl, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl,heteroaryl, and heterocycle;

provided that A² and A³, together with the B ring, are not

is a single bond or a double bond;

R¹ is heteroaryl, optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, —OR^(b),—S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, andheterocycle;

R and R² are independently chosen from H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, and heterocycle;

and each of said above alkyl, alkenyl, alkynyl, aryl, cycloalkyl,haloalkyl, heteroaryl and heterocycle can be optionally substituted byone or more groups independently chosen from optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are eachindependently chosen from H, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle,

or R^(a) and R^(c), and/or R^(c) and R^(d), and/or R^(c) and R^(e),and/or R^(c) and R^(f), and/or R^(d) and R^(e), and/or R^(g) and R^(f)together with the atom(s) to which they are attached, form a 3-10membered optionally substituted heterocycle ring; and

for each occurrence, n is independently 0, 1, or 2;

wherein each optionally substituted group above can be unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from, C₁-C₄ alkyl, cycloalkyl, oxo,aryl, heterocycle, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halo, —OH,—NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano,nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —C(O)Ocycloalkyl, —C(O)Oaryl,—C(O)Oheteroaryl, —C(O)Oheterocycle, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONR′R″ wherein R′ and R″ with the N to which they are attached form aheterocycle, —CON(cycloalkyl)(cycloalkyl),—CON(heterocycle)(heterocycle), —CONH(C₁-C₄ alkyl), —CONH(cycloalkyl),—CONH(heterocycle), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(cycloalkyl),—NHC(O)(heterocycle), —NHC(O)(aryl) such as —NHC(O)(phenyl),—NHC(O)(heteroaryl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(cycloalkyl), —N(C₁-C₄ alkyl)C(O)(heterocycle), —N(C₁-C₄alkyl)C(O)(aryl) such as —N(C₁-C₄ alkyl)C(O)(phenyl), —N(C₁-C₄alkyl)C(O)(heteroaryl), —C(O)C₁-C₄ alkyl, —C(O)(cycloalkyl),—C(O)(heterocycle), —C(O)(aryl) such as —C(O) phenyl, —C(O)(heteroaryl),—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)(cycloalkyl),—OC(O)(heterocycle), —OC(O)(heteroaryl), OC(O)(aryl) such as—OC(O)phenyl, —SO₂(C₁-C₄ alkyl), —SO₂(cycloalkyl), —SO₂(heterocycle),—SO₂(aryl) such as SO₂(phenyl), —SO₂(heteroaryl), —SO₂(C₁-C₄ haloalkyl),—SO₂NH₂, —SO₂NR′R″ wherein R′ and R″ with the N to which they areattached form a heterocycle, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(cycloalkyl),—SO₂NH(heterocycle), —SO₂NH(aryl) such as —SO₂NH(phenyl),—SO₂NH(heteroaryl), —NHSO₂(C₁-C₄ alkyl), NHSO₂(cycloalkyl),NHSO₂(heterocycle), NHSO₂(aryl) such as —NHSO₂(phenyl),—NHSO₂(heteroaryl), and —NHSO₂(C₁-C₄ haloalkyl), in which each of alkyl,phenyl, aryl, cycloalkyl, heterocycle, and heteroaryl is optionallysubstituted by one or more groups independently chosen from —OH, halo,cycloalkyl, heterocycle, C₁-C₄ alkyl, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl,C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, cyano,nitro, —NH₂, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), and —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl).

In some embodiments, A² and A³, together with B ring, are a 5-memberedheteroaryl or heterocycle containing 1 to 3 heteroatoms selected from N,O and S. In some embodiments, A² and A³, together with B ring, are a5-membered heteroaryl or heterocycle containing 1 to 3 nitrogenheteroatoms.

In some embodiments, A² and A³, together with B ring, can be selectedfrom structures (2)-(6)

wherein,

t is 1, 2 or 3; and

R³ is independently chosen from H, C₁-C₆alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₆-C₁₄aryl, C₃-C₉ cycloalkyl, —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, and heterocycle;

and each of said above alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heteroaryl and heterocycle can be optionally substituted by one or moregroups independently chosen from optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle, andR^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are as defined above.

provided that, when A² and A³, together with B ring, are structure (4),A⁴ is not CR², wherein R² is as defined above.

For example, R³ is independently chosen from H, OH, CN, NO₂, halo, C₁-C₆alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₆-C₁₄ aryl, C₃-C₉ cycloalkyl,heteroaryl, and heterocycle, wherein each of the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycle can be optionallysubstituted by one or more groups independently chosen from optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle;

In some embodiments, A² and A³ together with B ring, are chosen from thefollowing structures (2)-(5), wherein R³ and t are as defined above.

In some embodiments, A², A³ and together with the B ring, are chosenfrom structure (3)-(4), wherein R³ and t are as defined above.

In some embodiments, A⁴ is N or CH.

In some embodiments, A⁵ is N or CH.

In some embodiments, A₁, A₄, and A₅ are CH.

In some embodiments, A₁ and A₅ are CH, and A₄ is N.

In some embodiments, R¹ is a heteroaryl that is chosen from thefollowing structures

for example, R¹ is a heteroaryl chosen from

wherein each of which is optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,haloalkyl, heteroaryl, heterocycle, oxo, —C(O)R^(a), —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d) and halo, wherein each of the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl and heterocycle can beoptionally substituted by one or more groups independently chosen fromoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle;

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are eachindependently chosen from H, alkyl, aryl, cycloalkyl, haloalkyl,heteroaryl, and heterocycle, wherein each of the alkyl, aryl,cycloalkyl, heteroaryl, and heterocycle in R^(a), R^(b), R^(c), R^(d),R^(e), R^(f) and R^(g) is optionally substituted by one or more, such asone or two or three, substitutents independently selected from halo andalkyl.

In some embodiments, R¹ is

which is optionally substituted with one or more groups independentlychosen from:

alkyl, alkenyl, and alkynyl, wherein each of which can be optionallysubstituted by groups independently chosen from optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle;

C(O)NR^(c)R^(d); NR^(c)R^(d); OR^(b);

halo;cyano;

NR^(c)S(O)_(n)R^(e),

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are eachindependently chosen from H, alkyl, aryl, cycloalkyl, haloalkyl,heteroaryl, and heterocycle, for example, R^(a), R^(b), R^(c), R^(d),R^(e), R^(f) and R^(g) are each independently chosen from H, C₁-C₆alkyl, phenyl, C₃-C₆ cycloalkyl, C₁-C₃ haloalkyl, heteroaryl, andheterocycle, wherein each of the alkyl, aryl, cycloalkyl, heteroaryl,and heterocycle in R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) isoptionally substituted by one or more, such as one or two or three,substitutents independently selected from halo and alkyl.

Also provided is at least one compound selected from compounds 1 to 184and/or at least one pharmaceutically acceptable salt described herein.

The compounds described herein, and/or the pharmaceutically acceptablesalts thereof, can be synthesized from commercially available startingmaterials by methods well known in the art, taken together with thedisclosure in this patent application. The following schemes illustratemethods for preparation of some of the compounds disclosed herein.

The compounds thus obtained can be further modified at their peripheralpositions to provide the desired compounds. Synthetic chemistrytransformations are described, for example, in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagentsfor Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

Before use, the at least one compound and/or at least onepharmaceutically acceptable salt described herein, can be purified bycolumn chromatography, high performance liquid chromatography,crystallization, or other suitable methods.

Also provided is a composition comprising at least one compound and/orat least one pharmaceutically acceptable salt described herein, and atleast one pharmaceutically acceptable carrier.

A composition comprising at least one compound and/or at least onepharmaceutically acceptable salt described herein, can be administeredin various known manners, such as orally, parenterally, by inhalationspray, or via an implanted reservoir. The term “parenteral” as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

An oral composition can be any orally acceptable dosage form including,but not limited to, tablets, capsules, emulsions, and aqueoussuspensions, dispersions and solutions. Commonly used carriers fortablets include lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added to tablets. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.

A sterile injectable composition (e.g., aqueous or oleaginoussuspension) can be formulated according to techniques known in the artusing suitable dispersing or wetting agents (such as, for example, Tween80) and suspending agents. The sterile injectable preparation can alsobe a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the pharmaceutically acceptable vehicles andsolvents that can be employed are mannitol, water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium (e.g.,synthetic mono- or di-glycerides). Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agents.

An inhalation composition can be prepared according to techniques wellknown in the art of pharmaceutical formulation and can be prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A topical composition can be formulated in form of oil, cream, lotion,ointment and the like. Suitable carriers for the composition includevegetable or mineral oils, white petrolatum (white soft paraffin),branched chain fats or oils, animal fats and high molecular weightalcohols (greater than C12). In some embodiments, the pharmaceuticallyacceptable carrier is one in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thosetopical formulations. Examples of such enhancers can be found in U.S.Pat. Nos. 3,989,816 and 4,444,762.

Creams may be formulated from a mixture of mineral oil, self-emulsifyingbeeswax and water in which mixture the active ingredient, dissolved in asmall amount of an oil, such as almond oil, is admixed. An example ofsuch a cream is one which includes about 40 parts water, about 20 partsbeeswax, about 40 parts mineral oil and about 1 part almond oil.Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil, such as almond oil, with warm softparaffin and allowing the mixture to cool. An example of such anointment is one which includes about 30% by weight almond oil and about70% by weight white soft paraffin.

A pharmaceutically acceptable carrier refers to a carrier that iscompatible with active ingredients of the composition (and in someembodiments, capable of stabilizing the active ingredients) and notdeleterious to the subject to be treated. For example, solubilizingagents, such as cyclodextrins (which form specific, more solublecomplexes with the at least one compound and/or at least onepharmaceutically acceptable salt described herein), can be utilized aspharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10.

Suitable in vitro assays can be used to preliminarily evaluate theefficacy of the at least one compound and/or at least onepharmaceutically acceptable salt described herein, in inhibiting theactivity of PI3K and/or mTOR. The at least one compound and/or at leastone pharmaceutically acceptable salt described herein, can further beexamined for efficacy in treating cancer by in vivo assays. For example,the compounds described herein, and/or the pharmaceutically acceptablesalts thereof, can be administered to an animal (e.g., a mouse model)having cancer and its therapeutic effects can be accessed. Positiveresults in one or more of such tests are sufficient to increase thescientific storehouse of knowledge and hence sufficient to demonstratepractical utility of the compounds and/or salts tested. Based on theresults, an appropriate dosage range and administration route foranimals, such as humans, can also be determined.

Also provided is a method of inhibiting the activity of PI3K and/ormTOR. The method comprises contacting the enzyme with at least onecompound and/or at least one pharmaceutically acceptable salt describedherein in an amount effective to inhibit the activity of PI3K and/ormTOR.

The at least one compound and/or at least one pharmaceuticallyacceptable salt described herein can be used to achieve a beneficialtherapeutic or prophylactic effect, for example, in subjects withcancer. As used herein, the term “cancer” refers to a cellular disordercharacterized by uncontrolled or disregulated cell proliferation,decreased cellular differentiation, inappropriate ability to invadesurrounding tissue, and/or ability to establish new growth at ectopicsites. The term “cancer” includes, but is not limited to, solid tumorsand bloodborne tumors. The term “cancer” encompasses diseases of skin,tissues, organs, bone, cartilage, blood, and vessels. The term “cancer”further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladdercancer; colorectal cancer; breast cancer, including metastatic breastcancer; prostate cancer, including androgen-dependent andandrogen-independent prostate cancer; renal cancer, including, e.g.,metastatic renal cell carcinoma; hepatocellular cancer; lung cancer,including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolarcarcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer,including, e.g., progressive epithelial or primary peritoneal cancer;cervical cancer; gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck;skin cancer, including e.g., malignant melanoma; neuroendocrine cancer,including metastatic neuroendocrine tumors; brain tumors, including,e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma; bone cancer; soft tissuesarcoma; and thyroid carcinoma. For example, those solid tumors includepancreatic cancer; bladder cancer; colorectal cancer; breast cancer, andovarian cancer.

Non-limiting examples of hematologic malignancies include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the examples of the cancer to be treated include,but are not limited to, lung cancer, head and neck cancer, colorectalcancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer,prostate cancer, stomach cancer, kidney cancer, liver cancer, braincancer, bone cancer, and leukemia.

In some embodiments, the at least one compound and/or at least onepharmaceutically acceptable salt described herein, is administered inconjunction with another therapeutic agent. In some embodiments, theother therapeutic agent is one that is normally administered to patientswith the disease or condition being treated. The at least one compoundand/or at least one pharmaceutically acceptable salt described herein,may be administered with the other therapeutic agent in a single dosageform or as a separate dosage form. When administered as a separatedosage form, the other therapeutic agent may be administered prior to,at the same time as, or following administration of the at least onecompound and/or at least one pharmaceutically acceptable salt describedherein.

In some embodiments, at least one compound and/or at least onepharmaceutically acceptable salt described herein, is administered inconjunction with an anti-neoplastic agent. As used herein, the term“anti-neoplastic agent” refers to any agent that is administered to asubject with cancer for purposes of treating the cancer. Nonlimitingexamples of anti-neoplastic agents include: radiotherapy; immunotherapy;DNA damaging chemotherapeutic agents; and chemotherapeutic agents thatdisrupt cell replication.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide and related analogs (e.g., CC-5013 andCC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylateand gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa Binhibitors, including inhibitors of I kappa B kinase; antibodies whichbind to proteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdownregulates cell replication.

The examples below are intended to be purely exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Centigrade, and pressure is at or nearatmospheric. All MS data were checked by agilent 6120 and/or agilent1100. ¹H NMR spectra were recorded on Varian 400 MHz NMR spectrometerusing CDCl₃ or DMSO-d₆ as the solvent and tetramethylsilane (TMS) as theinternal standard. Chemical shifts (δ) were expressed in ppm downfieldfrom internal TMS, and J values were given in Hz. All reagents, exceptintermediates, used in this disclosure are commercially available. Allcompound names except the reagents were generated by Chemdraw 10.

In the following examples, the abbreviations below are used:

-   AcOH acetic acid-   DCM dichloromethane-   DMF N,N-dimethylformamide-   DMF-DMA 1,1-dimethoxy-N,N-dimethylmethanamine-   DMSO dimethyl sulfoxide-   DTT dithiothreitol-   EtOAc ethyl acetate-   h hour-   ISCO Flash chromatography-   mL milliliter(s)-   min minute(s)-   Py pyridine-   THF tetrahydrofuran-   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   DIPEA N,N-diisopropylethylamine-   DCM dichloromethane-   EA ethyl acetate-   PE petroleum ether-   Pd(dppf)Cl₂    1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride    dichloromethane complex-   PTLC preparative thin-layer chromatography-   HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid-   EGTA ethylene glycol tetraacetic acid)-   CHAPS 3-[(3-Cholamidopropyl)-dimethylammonio]-1-propanesulfonate-   TEA triethylamine-   TLC thin-layer chromatography

Intermediate 1 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile

To a solution of 2-chloro-5-nitropyridine (10 g, 63 mmol) in THF (150mL) at room temperature was added K₂CO₃ (17.4 g, 126 mmol) andtert-butyl 2-cyanoacetate (10.7 g, 76 mmol). The reaction mixture washeated to reflux and stirred overnight. Then the solid was filtered off,and the filtrate was concentrated to give the intermediate I-1 b (16.6g). m/z 208 (M+H)⁺.

The crude product tert-butyl 2-cyano-2-(5-nitropyridin-2-yl)acetate(I-1b, 12 g, 47 mmol) was dissolved in 100 mL of HCl/EtOH (v/v 1:5) andstirred at 80° C. for 4 h. Then the mixture was concentrated, dilutedwith H₂O, and extracted with EtOAc (4×40 mL). The combined extracts wereconcentrated, and the residue was purified by chromatography on silicagel (PE:EtOAc=3:1) to afford 2-(5-nitropyridin-2-yl)acetonitrile (I-1c)as a solid (7.7 g, 42.0% yield).

To the mixture of 2-(5-nitropyridin-2-yl)acetonitrile (I-1c, 8 g, 46mmol) and K₂CO₃ (18 g, 110 mmol) in CH₃CN (200 mL) was added iodomethane(7.5 mL, 120 mmol) dropwise at room temperature. The reaction mixturewas stirred at 40° C. overnight. Then the mixture was filtered, thefiltrate was concentrated, and the residue was purified bychromatography on silica gel (PE:EtOAc=5:1) to afford2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (I-1d) (4.2 g, 48%yield). m/z 192 (M+H)⁺.

The mixture of 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (I-1d, 2g, 10.4 mmol) and SnCl₂.2H₂O (9.3 g, 41.6 mmol) in EtOAc (10 mL) wasstirred at reflux for 4 h. After cooling to room temperature, aqueous 2M NaOH (80 mL) was added to adjust the pH to 8˜9, the solid was filteredoff, and the filtrate was extracted with ethyl acetate (3×40 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, andconcentrated to afford 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile(I-1) (1.7 g, 65.3% yield).

Intermediate 21,1,1-trifluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide

The mixture of2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.1 mmol) and Raney-Ni (10 mg) in MeOH (10 mL) wassubject to H₂ and stirred for 2 h. After filtration, the filtrate wasconcentrated to give the title compound as a white solid (261 mg).Yield: 95.0%.

To a solution of2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (100 mg, 0.4 mmol) and2,6-di-tert-butyl-4-methylpyridine (115 mg, 0.56 mmol) indichloromethane (5 mL) was added trifluoromethanesulfonic anhydride (147mg, 0.52 mmol) drop wise at −20° C., and the mixture was stirred at thistemperature for 2 h. Solvent was removed in vacuo and the residue wasused in the next step without further purification (141 mg). Yield:92.0%.

Intermediate 3 6-chloro-3-nitro-1,5-naphthyridin-4-ol

The mixture of 6-chloropyridin-3-amine (5.0 g, 38.8 mmol) and5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.2 g, 38.8mmol) in i-PrOH (60 mL) was stirred at reflux for 2 h, and the solventwas removed to afford5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a solid in 91% yield (10.0 g). m/z 283 (M+H)⁺

To the heated Dowtherm A (200 mL) at 200° C. was added5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(3.5 g, 12.4 mmol) and then stirred for additional 5 min. After coolingto r.t., PE was added. The precipitate was collected, and dried in vacuoto afford 6-chloro-1,5-naphthyridin-4-ol as off-white solid in 42% yield(0.94 g). m/z 183 (M+H)⁺

6-chloro-1,5-naphthyridin-4-ol (1.45 g, 8 mmol) was added to ice-cooledconc. H₂SO₄ (15 mL) and followed by the addition of KNO₃ (1.62 g, 16mmol) slowly at 0° C. The mixture was heated to 100° C. for 1 h, andthen was poured into ice-water. The precipitate was collected and driedin vacuo to afford 6-chloro-3-nitro-1,5-naphthyridin-4-ol as a solid in90% yield (1.97 g).

Intermediate 42,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

The mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.6 g, 25.8mmol), PdCl₂(dppf)-CH₂Cl₂ (500 mg) and potassium acetate (6.3 g, 64.5mmol) in anhydrous 1,4-dioxane (200 mL) was refluxed for 2 h. Then thesolvents were removed. The crude product was purified by chromatographyon silica gel using petroleum ether:EtOAc=10:1 as eluent to afford2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinein 81% yield (5 g). m/z 281 (M+H)⁺.

To the solution of2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.79 mmol) in MeOH (50 mL) was added Raney-Ni (50 mg).The reaction mixture was stirred at room temperature under H₂ for 2 h.Then the solid was filtered off, and the solvent was removed to afford2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-aminein 89% yield (400 mg). m/z 251 (M+H)⁺.

To the solution of2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(400 mg, 1.6 mmol) in pyridine (5 mL) was added2,4-difluorobenzenesulfonyl chloride (407 mg, 1.9 mmol) slowly, thereaction mixture was stirred at room temperature overnight, the solventwas evaporated in vacuo, and the residue was treated with brine (5 mL)and extracted with EtOAc (3×10 mL). The combined organic layer wasevaporated in vacuo, and the residue was purified by columnchromatography using petroleum ether:EtOAc=5:1 as eluent to afford thedesired product2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamideas white solid in 59% yield (400 mg). m/z 427 (M+H)⁺.

Intermediate 5 8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline

Bromine (0.895 mL, 15.5 mmol) was added to the solution ofquinoxalin-2-ol (1.5 g, 10.3 mmol) in HOAc (15 mL), the mixture wasstirred at r.t. for 6 h, and the precipitate was collected and washedwith ethyl ether and dried to afford 7-bromoquinoxalin-2-ol as a solidin 90% yield (2 g).

To the suspension of 7-bromoquinoxalin-2-ol (2 g, 8.88 mmol) in neatphosphorus oxychloride (7 mL) was added DMF (2 drops). The mixture washeated to 100° C. for 3 h. Then it was cooled to room temperature.Phosphorus oxychloride was removed under vacuum, and the residue wasdissolved into EtOAc and dropped into ice water with stirring. Themixture was extracted with EtOAc for three times, the combined organiclayer was washed with saturated NaHCO₃ solution. Then the organic layerwas concentrated to afford 7-bromo-2-chloroquinoxaline as a solid in 93%yield (2 g).

To the solution of 7-bromo-2-chloroquinoxaline (2 g, 8.2 mmol) inethanol (20 mL) was added hydrazine hydrate (85%, 4.5 mL, 32.8 mmol).The mixture was heated to 78° C. for 2 h. After cooling to r.t., theprecipitate was collected by filtration to afford7-bromo-2-hydrazinylquinoxaline as white solid in 87% yield (1.7 g).

The solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) intriethyl orthoformate (3 mL) was heated to 100° C. for 4 h; aftercooling to r.t., the mixture was diluted with ethyl ether, and theprecipitate was collected by filtration and dried in vacuo to afford thetitle product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline as yellow solidin 87% yield (180 mg). m/z 251 (M+H)⁺.

Intermediate 6 8-bromo-1-cyclopropyl-[1,2,4]triazolo[4,3-a]quinoxaline

To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol)in DMF (3 mL) was added HATU (380 mg, 1 mmol), DIPEA (0.205 mL, 1 mmol)and cyclopropanecarboxylic acid (71 mg, 0.83 mmol). After stirring atr.t. for 5 h, the mixture was diluted with EtOAc. The organic layer waswashed with water for three times, then concentrated to affordN′-(7-bromoquinoxalin-2-yl)cyclopropane-carbohydrazide as yellow solidwhich was used directly in the next step. m/z 309 (M+H)⁺.

The crude product N′-(7-bromoquinoxalin-2-yl)cyclopropanecarbohydrazidewas dissolved in HOAc (5 mL) and then heated to 100° C. overnight. Thesolvent was removed under vacuum and the residue was washed with waterand dried in vacuo to afford the title product8-bromo-1-cyclopropyl-[1,2,4]triazolo[4,3-a]quinoxaline as yellow solidin 42% overall yield (100 mg). m/z 291 (M+H)⁺.

Intermediate 7 8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one

To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol)in dichloromethane (5 mL) was added triethylamine (0.175 mL, 1.2 mmol),then the solution of diphosgene (0.055 mL, 0.46 mmol) in dichloromethanewas added dropwise at 0° C. with stirring under nitrogen atmosphere.After stirring at r.t. for 5 h, the solvent was removed under vacuum,the residue was washed with water, and dried in vacuo to afford thetitle product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one asyellow solid in 82% yield (180 mg). m/z 265 (M+H)⁺.

Intermediate 85-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine

An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g,16.60 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(5.90 g, 23.24 mmol), KOAc (4.07 g, 41.5 mmol) and PdCl₂(dppf).CH₂Cl₂(0.678 g, 0.830 mmol) in Dioxane (60 mL) was heated to 110° C. for 10 hunder N₂. After concentration under vacuum to remove the solvent, thecrude product was purified using a silica gel column, with PE/EtOAc aseluant to give pure product as pale yellow solid (4.5 g, yield 94%). MS(m/z): 289 (M+H)⁺.

EXAMPLE 1 Synthesis of Compounds 1-20 Compound 1(S)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one

To a suspension of 6-chloro-3-nitro-1,5-naphthyridin-4-ol (5 g, 22.1mmol) in 15 mL of DMF, was added a solution of phosphorous oxychloride(2.7 mL, 28.8 mmol) in anhydrous DMF (10 mL) over 3 min. The mixture wasstirred at room temperature overnight. The mixture was then poured ontocrushed ice. The resulting precipitate was collected by filtration,washed with H₂O, and dried in vacuo to afford2,8-dichloro-7-nitro-1,5-naphthyridine as yellow solid (4 g, yield74.0%). MS (m/z): 244 (M+H)⁺.

A mixture of 2,8-dichloro-7-nitro-1,5-naphthyridine (4 g, 16.4 mmol),4-amino-piperidine-1-carboxylic acid tert-butyl ester (4 g, 19.7 mmol)and triethylamine (3.5 mL) in DMF (15 mL) was stirred at roomtemperature overnight. The reaction mixture was poured into water (250mL). The precipitate was collected by filtration, washed with H₂O, anddried in vacuo to afford tert-butyl4-(6-chloro-3-nitro-1,5-naphthyridin-4-ylamino) piperidine-1-carboxylateas yellow solid (6.54 g, yield 97.8%). The crude product was used in thenext step without further purification. MS (m/z): 408 (M+H)⁺.

To the solution of tert-butyl4-(6-chloro-3-nitro-1,5-naphthyridin-4-ylamino) piperidine-1-carboxylate(6.43 g, 15.7 mmol) in EtOAc (250 mL) was added SnCl₂.2H₂O (18 g, 78.8mmol), and the mixture was stirred at room temperature for 3 h. Thensaturated NaHCO₃ was added to adjust the pH=8. The solid was filteredoff. The filtrate was concentrated and the crude product was purified bysilica gel chromatography using EtOAc:PE as eluant to afford tert-butyl4-(3-amino-6-chloro-1,5-naphthyridin-4-ylamino) piperidine-1-carboxylateas yellow solid in 85.6% yield (5.1 g). MS (m/z): 378 (M+H)⁺.

To a solution of tert-butyl4-(3-amino-6-chloro-1,5-naphthyridin-4-ylamino) piperidine-1-carboxylate(2.5 g, 6.6 mmol) in acetic acid (8 mL) was added NaNO₂ (460 mg, 6.6mmol) at 0° C. After the mixture was stirred at room temperature for 2hours, saturated sodium bicarbonate and ice water were added. Theresulting mixture was extracted with CH₂Cl₂. The organic layer was driedover anhydrous Na₂SO₄, and concentrated. The crude product was purifiedby silica gel chromatography using EtOAc:PE as eluant to affordtert-butyl 4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidine-1-carboxylate as yellow solid in 73.8% yield (1.9 g). MS(m/z): 388.8 (M+H)⁺.

A solution of tert-butyl4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidine-1-carboxylate (4 g) in CH₂Cl₂/MeOH was treated with 3 mLconc. HCl. The resulting solution was then concentrated to give8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridinehydrochloride as yellow solid. (3.81 g, yield 100%). MS (m/z): 289(M+H)⁺.

To a solution of8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridinehydrochloride (1 g, 3.08 mmol) in 10 mL of CH₂Cl₂ was added(S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et₃N (2.2mL). After the mixture was stirred at room temperature for 2 h, it wasquenched with water (10 mL). The resulting mixture was extracted withCH₂Cl₂ (2×20 mL). The combined organic layer was dried over anhydrousNa₂SO₄, and then was concentrated in vacuo to afford the(S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-ylacetate (1.2 g). MS (m/z): 403 (M+H)⁺.

To a solution of(S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-ylacetate (1.2 g, 2.97 mmol) in a mixture of THF (30 mL) and MeOH (30 mL),was added LiOH (650 mg, 14.9 mmol) drop-wise. The mixture was stirred atroom temperature for 3 h. After concentration in vacuo, the residue wasdiluted with water and the pH was adjusted to 7 with 2N HCl. Theresulting mixture was concentrated and the precipitate was collected byfiltration, washed with H₂O, and dried in vacuo to afford(S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-oneas yellow solid. The crude product was used in next step without furtherpurification. (918 mg, yield 85.4%). MS (m/z): 361 (M+H)⁺.

To a solution of(S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one(150 mg, 0.42 mmol) in a mixture of 20 mL dixoane and 2 mL H₂O was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(120 mg, 0.42 mmol), Pd(dppf)Cl₂ (20 mg, 0.02 mmol), and Na₂CO₃ (100 mg,0.84 mmol). The resulting mixture was purged with N₂ and stirred at 100°C. overnight, then the resulting mixture was purified on silica gelusing MeOH/H₂O as eluent to afford compound 1 as yellow solid (59.1 mg).¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.67 (s, 1H),8.64 (d, J=8.8 Hz, 1H), 8.54 (d, J=8.8 Hz, 1H), 7.09 (s, 2H), 6.23-6.02(m, 1H), 5.17-5.01 (m, 1H), 4.75-4.50 (m, 2H), 4.46-4.27 (m, 1H),3.00-2.79 (m, 1H), 2.39-1.90 (m, 3H), 1.36-1.16 (m, 6H). MS (m/z): 487(M+H)⁺.

The following compounds 2-20 were prepared according to the proceduresfor Compound 1 by using the corresponding intermediates and boronicacids or esters under appropriate conditions that could be recognized byone skilled in the art.

Compound Structure LC/MS NMR 2

418(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.35 (s, 1H), 8.68(d, J = 8.8 Hz, 1H), 8.53 (d, J = 8.8 Hz, 2H), 7.52-7.44 (m, 1H),6.09-5.90 (m, 1H), 5.19- 4.96 (m, 1H), 4.75-4.42 (m, 2H), 4.42-4.17 (m,1H), 3.11-2.91 (m, 1H), 2.55 (m, 3H), 2.42 (m, 4H), 1.23 (m, 3H). 3

433(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.52 (s, 1H), 8.82 (s, 1H), 8.54(d, J = 8.8 Hz, 1H), 8.37(d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 6.34 (s,2H), 6.13-5.96 (m, 1H), 5.79-5.66 (m, 1H), 5.17- 5.01 (m, 1H), 4.72-4.25(m, 3H), 3.14 (m, 5H), 3.04-2.93 (m, 1H), 2.16 (m, 7H), 1.23 (m,4H). 4

429(M + H)⁺ ¹H NMR (400 MHz, cd3od) δ 9.53 (s, 1H), 9.18-9.14 (m, 1H),8.75 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 8.9 Hz, 1H), 8.43 (d, J = 8.9 Hz,1H), 6.31- 6.03 (m, 1H), 3.58-3.48 (m, 2H), 3.40-3.36 (m, 1H), 3.30-3.26 (m, 1H), 2.76 (m, 3H), 2.68 (m, 4H). 5

434(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.60 (s, 1H), 9.02 (s, 1H), 8.70(d, J = 8.8 Hz, 1H), 8.35- 8.29 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H),7.01-6.92 (m, 1H), 6.22-5.98 (m, 1H), 4.89- 4.68 (m, 1H), 4.68-4.52 (m,1H), 4.23-4.08 (m, 1H), 4.07 (m, 3H), 3.59-3.39 (m, 1H), 3.38-3.14 (m,1H), 2.83- 2.45 (m, 5H), 1.43 (d, 3H). 6

471(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.58 (s, 1H), 9.06 (s, 1H), 8.66(d, J = 8.8 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H),6.15 (m, 1H), 5.31 (m, 2H), 4.93 (m, 1H), 4.22 (m, 1H), 3.41 (m, 1H),2.99 (m, 1H), 2.51 (m, 7H), 1.22 (m, 3H). 7

487(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.57 (s, 1H), 9.05 (s, 1H), 8.65(d, J = 8.8 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 6.15 (s,1H), 5.31 (s, 2H), 4.84 (m, 1H), 4.24 (m, 3H), 3.48 (m, 3H), 3.39 (m,1H), 3.12- 2.96 (m, 1H), 2.53 (m, 5H). 8

443(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 11.92 (s, 1H), 9.63 (s, 1H), 9.24(d, J = 2.0 Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.70 (d, J = 8.8 Hz, 1H),8.61 (d, J = 8.9 Hz, 1H), 7.60 (s, 1H), 6.65 (s, 1H), 6.08 (m, 1H),5.10-5.04 (m, 1H), 4.57 (m, 2H), 4.34 (m, 1H), 3.46 (m, 1H), 3.08 (m,1H), 2.29 (m, 3H), 1.26 (m, 3H). 9

483(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.58 (s, 1H), 9.07 (d, J = 2.0 Hz,1H), 8.66 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.17 (d, J =8.8 Hz, 1H), 6.17 (s, 1H), 5.32 (m, 3H), 4.88 (m, 1H), 4.57 (m, 1H),3.50 (m, 1H), 3.06 (m, 1H), 2.52 (m, 5H), 1.32 (m, 2H), 1.06 (m, 2H),0.90 (m, 2H). 10

416(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.58 (s, 1H), 9.08 (s, 1H), 8.65(d, J = 8.9 Hz, 2H), 8.17 (d, J = 8.8 Hz, 1H), 6.21-5.97 (m, 1H), 5.33(s, 2H), 4.30 (m, 2H), 3.76 (m, 2H), 2.85-2.56 (m, 2H), 2.38 (m, 2H). 11

433(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.57 (s, 1H), 8.74 (s, 1H), 8.63(d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 12.5 Hz,1H), 6.09 (s, 1H), 5.06-4.93 (m, 2H), 4.85 (m, 1H), 4.54 (m, 1H), 3.57(sm, 1H), 3.10 (m, 1H), 2.54 (m, 5H), 1.86 (m, 1H), 1.07 (m, 2H), 0.85(m, 2H). 12

372(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.55 (s, 1H), 8.35 (d, J = 2.3,1H), 8.27 (d, J = 1.8, 1H), 8.22 (s, 1H), 8.10 (dd, J = 8.7, 2.0, 1H),7.76-7.71 (m, 2H), 7.37 (t, J = 8.9, 1H), 7.10-7.06 (m, 1H), 6.61 (d, J= 8.6, 1H), 6.54 (s, 2H), 6.27 (s, 2H). 13

374(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.62 (s, 1H), 8.42 (s, 2H), 8.29(d, J = 8.7, 1H), 8.19-8.13 (m, 2H), 7.91 (dd, J = 15.2, 8.0, 2H), 7.82(d, J = 8.0, 1H), 7.71 (s, 1H), 6.94 (s, 2H). 14

447(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 13.61 (s, 1H), 9.63 (s, 1H), 8.37(s, 1H), 8.31-8.25 (m, 3H), 8.18 (dd, J = 8.8, 1.8 Hz, 1H), 7.90 (d, J =8.7 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.63 (s, 2H), 6.70 (s, 2H). 15

456(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.49 (s, 1H), 8.77 (s, 1H), 8.57(s, 1H), 8.28 (d, J = 8.7, 1H), 8.23-8.16 (m, 2H), 6.70 (s, 2H), 5.80(t, J = 10.7, 1H), 4.50 (d, J = 13.3, 1H), 4.02 (d, J = 13.5, 2H), 3.04(t, J = 11.6, 1H), 2.40 (s, 2H), 2.31-2.20 (m, 1H), 2.10-2.02 (m, 4H).16

476(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.72 (s, 1H), 9.24 (s, 1H), 8.87(s, 1H), 8.65 (s, 2H), 8.53 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 6.98(s, 2H), 1.86 (s, 6H). 17

475(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.71 (s, 1H), 8.90 (d, J = 1.9,1H), 8.65 (d, J = 8.9, 1H), 8.52 (d, J = 8.9, 1H), 8.49-8.40 (m, 1H),8.26 (d, J = 1.9, 1H), 8.09 (d, J = 8.6, 2H), 7.85 (d, J = 8.6, 2H),6.99 (s, 2H), 1.84 (s, 6H). 18

408(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.69 (s, 1H), 8.76 (s, 2H), 8.61(d, J = 8.9, 1H), 8.41 (d, J = 8.9, 1H), 8.03 (d, J = 8.4, 2H), 7.88 (d,J = 8.4, 2H), 7.14 (s, 2H), 1.88 (s, 6H). 19

443(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.58 (s, 1H), 9.19 (s, 1H), 8.67(s, 1H), 8.62 (d, J = 8.8, 1H), 8.53 (d, J = 8.9, 1H), 7.11 (s, 2H),5.88-5.77 (m, 1H), 3.19- 3.14 (m, 2H), 2.49-2.44 (m, 2H), 2.37-2.32 (m,4H), 2.24-2.21 (m, 2H), 1.10 (t, J = 7.1, 3H). 20

469(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.59 (s, 1H), 9.19 (d, J = 1.8,1H), 8.68 (d, J = 1.9, 1H), 8.62 (d, J = 8.9, 1H), 8.53 (d, J = 8.9,1H), 7.10 (s, 2H), 5.87- 5.76 (m, 1H), 3.28 (d, J = 11.3, 2H), 2.40-2.33(m, 4H), 2.32-2.31 (m, 2H), 2.29- 2.21 (m, 2H), 0.92-0.91 (m, 1H),0.55-0.47 (m, 2H), 0.18- 0.09 (m, 2H).

EXAMPLE 2 Synthesis of Compounds 21-29 Compound 21(R)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one

To a solution of8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridinehydrochloride (600 mg, 1.85 mmol) in DMF (15 mL) was added(R)-2-hydroxypropanoic acid (540 mg, 1.85 mmol), HATU (850 mg, 2.21mmol) and DIEA (0.8 mL, 3.70 mmol). The mixture was stirred at roomtemperature overnight. Another 3 eq of HATU and 2 eq of DIEA were addedbecause the reaction did not go to completion as shown by HPLC-MS. Themixture was stirred for another 30 min, and was then diluted with water.The resulting mixture was extracted with ethyl acetate twice. Thecombined organic layers were dried over anhydrous Na₂SO₄, andconcentrated to give the crude product, which was subsequently purifiedby chromatography on silica gel using EtOAc:PE as eluent to afford(R)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-oneas a yellow solid (136 mg, yield 20.4%). MS (m/z): 361 (M+H)⁺.

The next step for the synthesis of compound 21 was similar to thecorresponding step used for the synthesis of Compound 1.

Compound 21: a solid, 31.0 mg. ¹H NMR (400 MHz, dmso) δ 9.59 (s, 1H),9.19 (s, 1H), 8.66 (s, 1H), 8.63 (d, J=8.9 Hz, 1H), 8.53 (d, J=8.9 Hz,1H), 7.07 (s, 2H), 6.09 (m, 1H), 5.02 (m, 1H), 4.74-4.27 (m, 2H), 2.87(m, 1H), 2.44-1.90 (m, 3H), 1.27-1.21 (m, 4H). MS (m/z): 487 (M+H)⁺.

The following compounds 22-29 were prepared according to the proceduresfor Compound 21 by using the corresponding intermediates and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art.

Compound Structure LC/MS NMR 22

433(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.53 (s, 1H), 8.82 (s, 1H), 8.55(d, J = 8.9 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.17 (s, 1H), 6.34 (s,2H), 6.02 (m, 1H), 5.06 (m, 1H), 4.55 (m 2H), 4.32 (m, 1H), 2.99 (s,1H), 2.29 (m, 1H), 2.17 (m, 5H), 1.97 (m, 1H), 1.23 (m, 3H). 23

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.52 (s, 1H), 8.80 (s, 1H), 8.61(s, 1H), 8.29 (d, J = 8.7, 1H), 8.22 (d, J = 6.4, 2H), 6.75 (s, 2H),5.86 (s, 1H), 5.10-4.91 (m, 1H), 4.51 (s, 2H), 4.25 (s, 1H), 3.57-3.43(m, 2H), 3.12 (d, J = 12.4, 2H), 2.35-2.18 (m, 1H), 2.08 (s, 1H), 1.22(s, 3H). 24

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 8.16 (s, 1H), 7.80 (d, J = 8.2,1H), 7.40 (s, 3H), 7.27 (t, J = 7.6, 2H), 7.16 (d, J = 7.4, 1H), 7.04(d, J = 7.2, 1H), 6.97 (t, J = 8.0, 1H), 6.35-6.13 (m, 1H), 5.34-5.10(m, 1H), 3.80 (s, 3H), 2.20 (s, 3H), 1.44 (d, J = 6.3, 3H). 25

473(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.62 (s, 1H), 9.22 (d, J = 1.6 Hz,1H), 8.69 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 8.9 Hz, 1H), 8.56 (d, J =8.9 Hz, 1H), 7.09 (s, 2H), 6.13 (s, 1H), 5.34 (m, 1H), 4.65 (m, 2H),4.17 (m, 3H), 2.94 (m, 2H), 2.07 (m, 4H). 26

501(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.59 (s, 1H), 9.21 (d, J = 2.2 Hz,1H), 8.67 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.16 (d, J =8.8 Hz, 1H), 5.98 (s, 1H), 5.30 (m, 2H), 4.97- 4.88 (m, 3H), 3.22 (m,2H), 2.80 (m, 2H), 2.41 (m, 2H), 1.62 (m, 6H). 27

500(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.62 (s, 1H), 9.21 (s, 1H), 8.73-8.63 (m, 2H), 8.56 (d, J = 8.9 Hz, 1H), 7.11 (s, 2H), 6.19- 6.05 (m,1H), 4.91-4.79 (m, 2H), 3.24-3.11 (m, 2H), 2.47- 2.43 (mz, 2H),2.29-2.19 (m, 2H), 1.49 (s, 6H). 28

469(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.58 (s, 1H), 9.18 (s, 1H), 8.65(s, 1H), 8.62 (d, J = 8.9 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 7.08 (m,2H), 6.89 (d, J = 6.0 Hz, 1H), 6.22-5.99 (m, 2H), 5.71 (m, 1H), 4.62 (m,1H), 4.34 (m, 1H), 3.37 (m, 3H), 2.95 (m, 1H), 2.35-1.84 (m, 3H). 29

415(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.53 (s, 1H), 8.82 (d, J = 2.1 Hz,1H), 8.55 (d, J = 8.9 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.17 (s, 1H),6.98-6.85 (m, 1H), 6.35 (s, 2H), 6.23-6.09 (m, 1H), 6.09-5.96 (m, 1H),5.75-5.67 (m, 1H), 5.37-5.21 (m, 1H), 4.76-4.62 (m, 1H), 4.46-4.30 (m,1H), 4.18-4.02 (m, 1H), 3.10-2.98 (m, 1H), 2.55-2.50 (m, 1H), 2.16 (m,6H).

EXAMPLE 3 Synthesis of Compounds 30-42 Compound 301-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-one

A mixture of8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine(200 mg, 0.69 mmol), isobutyric acid (67 mg, 0.76 mmol), HATU (315 mg,0.83 mmol) and DIEA (133 mg, 1.04 mmol) in DMF (5 mL) was stirred atr.t. overnight. Then water (10 mL) was added; the precipitate wascollected and dried in vacuo to afford1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-oneas a solid (200 mg).

A mixture of1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-one(60 mg, 0.17 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(53 mg, 0.18 mmol), K₂CO₃ (70 mg, 0.51 mmol) and Pd(dppf)Cl₂ (6 mg) indioxane/H₂O (3:1, 4 mL) was stirred and microwaved at 160° C. for 0.5 h.The solvent was removed, and the residue was purified by ISCO(MeOH/H₂O=20%-80%) to afford1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-oneas white solid (46 mg). ¹HNMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.21 (d,J=2.1 Hz, 1H), 8.66 (dd, J=12.5, 5.5 Hz, 2H), 8.55 (d, J=8.9 Hz, 1H),7.10 (s, 2H), 6.17-6.01 (m, 1H), 4.78-4.59 (m, 1H), 4.35-4.26 (m, 1H),3.40-3.37 (m, 2H), 3.05-2.97 (m, 1H), 2.93-2.82 (m, 1H), 2.64-2.52 (m,1H), 2.39-2.21 (m, 1H), 2.16-1.96 (m, 1H), 1.07 (s, 6H). MS (m/z): 485(M+H)⁺.

The following compounds 31-42 were prepared according to the proceduresfor Compound 30 by using the corresponding intermediates and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art.

Compound Structure LC/MS NMR 31

435(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.59 (s, 1H), 8.83 (s, 1H), 8.61 (d,J = 8.9 Hz, 1H), 8.45 (d, J = 8.9 Hz, 1H), 8.25 (dd, J = 12.7, 1.8 Hz,1H), 6.87 (s, 2H), 6.15-5.91 (m, 1H), 4.68 (d, J = 12.7 Hz, 1H), 4.29(d, J = 12.0 Hz, 1H), 3.49-3.38 (m, 2H), 3.06-2.95 (m, 2H), 2.58-2.52(m, 1H), 2.36-2.24 (m, 1H), 2.17-2.05 (m, 1H), 1.07 (d, J = 6.4 Hz, 6H).32

415(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.22 (s, 1H), 8.65 (d,J = 8.9 Hz, 2H), 8.55 (d, J = 8.9 Hz, 1H), 8.25 (s, 2H), 7.11 (s, 2H),6.09-5.96 (m, 1H), 3.43 (d, J = 13.4 Hz, 2H), 2.99 (t, J = 11.4 Hz, 2H),2.46-2.31 (m, 4H). 33

508(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.63 (s, 1H), 9.23 (s, 1H), 8.67 (d,J = 9.0 Hz, 2H), 8.56 (d, J = 8.9 Hz, 1H), 7.09 (s, 2H), 6.21-6.12 (m,1H), 4.61-4.48 (m, 2H), 3.40-3.52 (m, 2H), 2.61-2.53 (m, 2H), 2.41-2.27(m, 2H), 1.68- 1.56 (m, 4H). 34

500(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.21 (s, 1H),8.74-8.61 (m, 2H), 8.55 (d, J = 8.9 Hz, 1H), 7.10 (s, 2H), 6.18-6.07 (m,1H), 4.65 (d, J = 12.6 Hz, 1H), 4.24 (d, J = 12.7 Hz, 1H), 3.67 (d, J =14.0 Hz, 1H), 3.57 (d, J = 14.1 Hz, 1H), 3.36 (dd, J = 32.3, 20.7 Hz,2H), 2.95 (t, J = 12.3 Hz, 1H), 2.45 (s, 6H), 2.40-2.33 (m, 1H),2.22-2.07 (m, 2H). 35

485(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 9.11 (s, 1H),8.58-8.45 (m, 3H), 7.03 (s, 2H), 5.98 (s, 1H), 4.64 (s, 1H), 4.16 (s,1H), 2.38 (s, 4H), 2.05 (s, 2H), 1.54 (s, 2H), 1.17 (s, 2H), 0.89 (s,3H). 36

540(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.58 (s, 1H), 9.06 (s, 1H), 8.66(d, J = 9.0, 1H), 8.60 (s, 1H), 8.17 (d, J = 8.8, 1H), 6.20-6.08 (m,1H), 5.33 (s, 2H), 4.96-4.85 (m, 1H), 4.30-4.19 (m, 1H), 3.49-3.38 (m,1H), 2.95 (m, 3H), 2.55 (m, 4H), 2.30 (m, 3H), 2.00 (m, 4H), 1.80 (m,2H). 37

499(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.53 (s, 1H), 9.13 (s, 1H), 8.54(m, 3H), 7.06 (s, 2H), 6.01 (s, 1H), 4.64 (s, 1H), 4.18 (s, 1H),2.43-1.92 (m, 7H), 1.50 (s, 2H), 1.25 (m, 3H), 0.87 (s, 3H). 38

497(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.39 (s, 1H), 9.00 (s, 1H), 8.44(m, 2H), 8.34 (m, 1H), 6.91 (s, 2H), 5.88 (m, 1H), 4.50 (m, 1H), 3.99(m, 1H), 2.14 (m, 7H), 1.04 (m, 1H), 0.84 (m, 1H), 0.32 (m, 2H), 0.00(m, 2H). 39

499(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.62 (s, 1H), 9.21 (s, 1H), 8.66 (d,J = 8.7 Hz, 2H), 8.56 (d, J = 8.9 Hz, 1H), 7.10 (s, 2H), 6.21-6.09 (m,1H), 4.61-4.49 (m, 1H), 3.95-3.81 (m, 1H), 3.45- 3.36 (m, 1H), 3.17-3.07(m, 1H), 2.85 (q, J = 7.2 Hz, 2H), 2.62-2.54 (m, 2H), 2.41-2.31 (m, 1H),2.25-2.18 cm, 1H), 1.07 (t, J = 7.2 Hz, 2H). 40

520(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.62 (s, 1H), 9.22 (d, J = 1.9,1H), 8.69-8.63 (m, 3H), 8.56 (d, J = 8.9, 1H), 7.97 (td, J = 7.7, 1.7,1H), 7.69 (d, J = 7.8, 1H), 7.53-7.50 (m, 1H), 7.11 (s, 2H), 6.21-6.18(m, 1H), 4.88-4.75 (m, 1H), 4.03-4.01 (m, 1H), 2.59-2.51 cm, 3H),2.46-2.32 (m, 3H). 41

519(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.21 (d, J = 2.1,1H), 8.65 (t, J = 5.5, 2H), 8.54 (d, J = 8.9, 1H), 7.55- 7.46 (m, 5H),7.10 (s, 2H), 6.18-6.07 (m, 1H), 4.95-4.57 (m, 1H), 4.01- 3.74 (m, 1H),2.57-2.54 (m, 1H), 2.48-2.45 (m, 1H), 2.38-2.28 (m, 3H), 2.08-1.91 (m,1H). 42

437(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.00 (s, 1H), 8.93 (d, J = 1.8,1H), 8.30-8.20 (m, 3H), 8.08 (d, J = 8.9, 1H), 7.98 (d, J = 8.4, 1H),7.88 (d, J = 8.9, 1H), 6.92 (d, J = 25.9, 3H), 3.61 (s, 3H), 1.83 (s,6H).

EXAMPLE 4 Synthesis of Compounds 43-47 Compound 432-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-N,N-dimethylacetamide

A mixture of8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine(100 mg, 0.35 mmol), 2-chloro-N,N-dimethylacetamide (46 mg, 0.38 mmol),and K₂CO₃ (97 mg, 1.04 mmol) in DMF (5 mL) was stirred at r.t.overnight. The solvent was removed, and the residue was extracted withEtOAc (3×10 mL). The combined organic layers were dried over Na₂SO₄, andconcentrated to afford crude2-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-N,N-dimethylacetamide,which was used in the next step without further purification.

A mixture of the above product,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(109 mg, 0.38 mmol), K₂CO₃ (145 mg, 1.05 mmol) and Pd(dppf)Cl₂ (10 mg)in dioxane/H₂O (3:1, 4 mL) was stirred and microwaved at 160° C. for 0.5h. The solvent was removed, and the residue was purified bychromatography to afford compound 43 as a pale yellow solid (50 mg).¹HNMR (400 MHz, dmso-d₆) δ 9.60 (s, 1H), 9.20 (d, J=2.0 Hz, 1H), 8.66(dd, J=16.5, 5.4 Hz, 2H), 8.54 (d, J=8.9 Hz, 1H), 7.12 (s, 2H),5.97-5.77 (m, 1H), 3.40 (s, 2H), 3.29-3.14 (m, 4H), 3.10 (s, 3H), 2.86(s, 3H), 2.44-2.35 (m, 4H). MS (m/z): 500 (M+H)⁺.

The following compounds 44-47 were prepared according to the proceduresfor Compound 43 by using the corresponding intermediates, and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art:

Compound Structure LC/MS NMR 44

499(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.60 (s, 1H), 9.21 (d, J = 2.0,1H), 8.71 (d, J = 2.1, 1H), 8.64 (d, J = 8.9, 1H), 8.55 (d, J = 8.9,1H), 7.13 (s, 2H), 4.41 (d, J = 5.7, 2H), 4.25 (d, J = 5.7, 2H), 2.62(s, 2H), 2.40-2.21 (m, 8H), 1.38 (s, 3H). 45

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.57 (s, 1H), 9.18 (d, J = 2.1,1H), 8.65 (s, 1H), 8.62 (d, J = 8.9, 1H), 8.51 (d, J = 8.9, 1H), 7.07(s, 2H), 6.66 (t, J = 5.4, 1H), 6.01 (s, 1H), 4.23 (d, J = 14.0, 2H),2.93 (t, J = 12.2, 2H), 2.36-2.34 (m, 2H), 2.14-2.12 (m, 2H), 1.98-1.96(m, 2H), 1.02 (t, J = 7.1, 3H). 46

459(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.73- 9.68 (m, 1H), 9.57 (s, 1H),8.64 (d, J = 8.8 Hz, 1H), 8.53-8.48 (m, 1H), 8.15 (d, J = 8.8 Hz, 1H),5.75- 5.60 (m, 1H), 5.40 (s, 2H), 3.78- 3.71 (m, 2H), 3.34-3.26 (m, 2H),3.21-3.07 (m, 2H), 2.76-2.65 (m, 2H), 2.48-2.34 (m, 2H), 1.31 (m, 4H).47

505(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.57 (s, 1H), 9.18 (s, 1H), 8.67(s, 1H), 8.61 (d, J = 8.7, 1H), 8.51 (d, J = 9.2, 2H), 7.79 (s, 1H),7.53 (d, J = 7.4, 1H), 7.27 (s, 1H), 7.09 (s, 2H), 5.94-5.81 (m, 1H),3.71 (s 2H), 3.13 (m, 2H), 2.35 (s, 6H).

EXAMPLE 5 Synthesis of Compound 48 Compound 485-(1-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-8-yl)-3-(trifluoromethyl)pyridin-2-amine

Under N₂, a white suspension of8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine(130 mg, 0.450 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (97 mg, 0.540mmol) and K₂CO₃ (124 mg, 0.900 mmol) in acetonitrile (15 mL) was heatedto reflux for 4 h. After cooling to room temperature, the mixture wasdiluted with EtOAc 20 mL. The mixture was then filtered through aBuchner funnel, and the organic phase was collected and concentrated.The crude product was used in the next step without further purification(35 mg). MS (m/z): 387 (M+H)⁺.

Under N₂, an orange suspension of8-chloro-1-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine(35 mg, 0.090 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(26.1 mg, 0.090 mmol), Na₂CO₃ (19.18 mg, 0.181 mmol) andPdCl₂(dppf).CH₂Cl₂ (3.69 mg, 4.52 μmol) in a mixture of dioxane (20 mL)and H₂O (2 mL) was stirred for 10 minutes, before the resulting mixturewas heated to 120° C. for 2 h. After concentration in vacuo, theresulting residue was purified by ISCO with 12 g silica gel (PE/EtOAc)to give the product as pale yellow powder (10 mg). ¹H NMR (400 MHz,dmso) δ 9.53 (s, 1H), 9.15 (d, J=2.1, 1H), 8.65 (s, 1H), 8.61 (d, J=8.9,1H), 8.51 (d, J=8.9, 1H), 7.07 (s, 2H), 5.99-5.80 (m, 1H), 3.91-3.85 (m,4H), 3.22-3.08 (m, 4H), 2.41-2.15 (m, 10H), 1.73-1.58 (m, 2H). MS (m/z):513 (M+H)⁺.

EXAMPLE 6 Synthesis of Compounds 49-78 Compound 492-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)phenyl)-2-methylpropanenitrile

To a solution of 7-bromo-2-hydrazinylquinoxaline (1.5 g, 0.063 mol) and4-(2-cyanopropan-2-yl) benzoic acid (1.1 g, 0.063 mol) in DMF (5 mL) wasadded HATU (2.4 g, 0.063 mol) and DIEA (1.2 g, 0.095 mol). The reactionmixture was then stirred at r.t. overnight. The solution was dilutedwith water (5 mL), and the solid was collected on a filter to giveN′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide as ayellow solid (2.2 g, yield 85.0%). MS (m/z): 412 (M+H)⁺.

A solution ofN′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide (2.2 g,0.054 mol) in 3 mL of AcOH was stirred at 100° C. overnight. Aftercooling to room temperature, the reaction mixture was diluted with water(5 mL). The solid was collected on a filter, and washed with Sat. NaHCO₃(5 mL) to give 2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)phenyl)-2-methylpropanenitrile as a yellow solid (1.8 g, yield 85.0%).MS (m/z): 392 (M+H)⁺.

To a mixture of2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)phenyl)-2-methylpropanenitrile(80 mg, 0.21 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(59 mg, 0.21 mmol) and K₂CO₃ (87 mg, 0.63 mmol) in dioxane (3 mL) andH₂O (1 mL) was added Pd(dppf)Cl₂ (3 mg). The reaction mixture wasmicrowaved at 150° C. for 30 min. After cooling to room temperature, themixture was concentrated and purified by chromatography to give compound49 as a yellow solid (52 mg). ¹H NMR (400 MHz, dmso) δ 9.38 (s, 1H),8.26 (s, 1H), 8.11 (d, J=8.5, 1H), 7.99-7.95 (m, 1H), 7.92 (d, J=8.3,2H), 7.83 (d, J=8.4, 2H), 7.63 (m, 1H), 7.52 (d, J=1.5, 1H), 6.77 (s,2H), 1.77 (s, 6H). MS (m/z): 474 (M+H)⁺.

The following compounds 50-78 were prepared according to the proceduresfor Compound 49 by using the corresponding intermediates and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art.

Compound Structure LC/MS NMR 50

406(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.38 (s, 1H), 8.12 (d, J = 8.5,1H), 7.96- 7.87 (m, 5H), 7.74 (d, J = 1.8, 1H), 7.64 (s, 2H), 7.55 (d, J= 1.8, 1H), 7.27 (d, J = 8.4, 1H), 7.10 (dd, J = 8.4, 2.0, 1H), 1.81 (s,6H). 51

392(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 9.21 (s, 1H), 8.80(s, 2H), 8.27 (d, J = 8.4, 1H), 8.16 (dd, J = 8.4, 1.9, 1H), 7.92 (dd, J= 11.7, 2.9, 5H), 7.49 (d, J = 1.8, 1H), 1.84 (s, 6H). 52

462(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.38 (s, 1H), 8.12 (d, J = 8.5,1H), 7.96- 7.87 (m, 5H), 7.74 (d, J = 1.8, 1H), 7.64 (s, 2H), 7.55 (d, J= 1.8, 1H), 7.27 (d, J = 8.4, 1H), 7.10 (dd, J = 8.4, 2.0, 1H), 1.81 (s,6H). 53

431(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 13.81 (s, 1H), 9.43 (s, 1H), 8.46(d, J = 2.2 Hz, 1H), 8.21-8.16 (m, 2H), 8.14 (s, 1H), 8.06 (dd, J = 8.5,1.9 Hz, 1H), 7.92 (q, J = 8.5 Hz, 4H), 7.53 (d, J = 1.8 Hz, 1H), 1.79(s, 6H). 54

475(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.47 (s, 1H), 9.09 (dd, J = 2.3,0.8, 1H), 8.50 (dd, J = 8.2, 2.3, 1H), 8.35 (d, J = 2.2, 1H), 8.19 (d, J= 8.5, 1H), 8.08-8.02 (m, 1H), 7.96 (dd, J = 8.2, 0.8, 1H), 7.71 (d, J =2.2, 1H), 7.55 (d, J = 1.9, 1H), 6.83 (s, 2H), 1.82 (s, 6H). 55

446(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.38 (s, 1H), 8.11 (d, J = 8.5,1H), 7.96 (dd, J = 8.5, 1.7, 1H), 7.90 (q, J = 8.5, 4H), 7.55 (s, 2H),7.48 (d, J = 1.6, 1H), 7.38 (d, J = 1.3, 1H), 7.12 (d, J = 8.1, 1H),7.00 (dd, J = 8.2, 1.5, 1H), 1.82 (s, 6H). 56

463(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.43 (s, 1H), 9.09 (s, 1H), 8.45(dd, J = 8.2, 2.2, 1H), 8.16 (d, J = 8.5, 1H), 8.04-7.96 (m, 2H), 7.76(d, J = 1.9, 1H), 7.66 (s, 2H), 7.53 (d, J = 1.8, 1H), 7.30 (d, J = 8.4,1H), 7.16 (dd, J = 8.4, 2.0, 1H), 1.83 (s, 6H). 57

421(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.39 (s, 1H), 9.07 (s, 1H), 8.45(dd, J = 8.2, 2.3, 1H), 8.11 (d, J = 8.5, 1H), 8.00 (d, J = 8.2, 1H),7.94- 7.87 (m, 2H), 7.44 (d, J = 1.8, 1H), 7.23 (d, J = 1.7, 1H), 6.08(s, 2H), 2.04 (s, 3H), 1.82 (s, 6H). 58

420(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.35 (s, 1H), 8.14 (s, 1H), 8.08(d, J = 8.5, 1H), 7.94-7.84 (m, 6H), 7.47 (d, J = 1.8, 1H), 7.20 (d, J =1.7, 1H), 6.05 (s, 2H), 2.03 (s, 3H), 1.81 (s, 6H). 59

426(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 8.99 (d, J = 2.8,1H), 8.58 (d, J = 2.1, 1H), 8.33-8.29 (m, 1H), 8.25-8.21 (m, 2H), 8.15(d, J = 8.5, 1H), 8.05 (d, J = 1.8, 1H), 7.84 (d, J = 2.2, 1H), 6.93 (s,2H). 60

414(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.50 (s, 1H), 9.13 (d, J = 2.8,1H), 8.32- 8.29 (m, 1H), 8.24-8.19 (m, 3H), 8.08 (dd, J = 8.5, 1.9, 1H),7.94 (s, 1H), 7.74 (s, 2H), 7.46 (d, J = 2.4, 2H). 61

430(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 13.18 (s, 1H), 9.41 (s, 1H), 8.16(d, J = 8.5, 1H), 8.09 (s, 1H), 8.01 (dd, J = 8.5, 1.9, 1H), 7.96-7.90(m, 4H), 7.81 (s, 1H), 7.59 (d, J = 1.9, 1H), 7.54 (d, J = 8.7, 1H),7.30 (dd, J = 8.7, 1.6, 1H), 1.79 (s, 6H). 62

432(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.45 (s, 1H), 8.42 (s, 1H), 8.36(d, J = 2.0, 1H), 8.27-8.22 (m, 2H), 8.18 (d, J = 8.5, 1H), 8.07 (dd, J= 8.5, 1.8, 1H), 7.94 (t, J = 7.8, 1H), 7.60 (d, J = 2.1, 1H), 7.42 (d,J = 1.8, 1H), 6.88 (s, 2H). 63

420(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.42 (s, 1H), 8.49 (s, 1H),8.29-8.10 (m, 3H), 7.95 (s, 2H), 7.69 (d, J = 8.1, 3H), 7.51 (s, 1H),7.32 (d, J = 7.1, 1H), 7.21 (s, 1H). 64

432(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.45 (s, 1H), 8.44 (d, J = 2.2,1H), 8.21 (d, J = 1.8, 1H), 8.19 (d, J = 3.0, 1H), 8.17 (s, 1H), 8.13(d, J = 1.9, 1H), 8.12 (d, J = 1.9, 1H), 8.07 (dd, J = 8.5, 1.9, 1H),7.56 (d, J = 2.2, 1H), 7.46 (d, J = 1.9, 1H), 6.87 (s, 2H). 65

422(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.40 (s, 1H), 8.88 (s, 1H), 8.41(s, 2H), 8.21 (d, J = 8.1, 1H), 8.14 (d, J = 8.4, 1H), 8.02 (d, J = 7.9,1H), 7.62-7.54 (m, 2H), 7.48 (s, 1H), 6.83 (s, 2H), 2.63 (s, 3H). 66

424(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.37 (s, 1H), 8.09 (d, J = 8.5,1H), 7.94 (d, J = 8.8, 1H), 7.89 (d, J = 1.8, 3H), 7.87 (s, 1H), 7.83(s, 1H), 7.37 (s, 1H), 7.21 (d, J = 12.5, 1H), 6.57 (s, 2H), 1.81 (s,6H). 67

447(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 9.18 (d, J = 1.6,1H), 8.51 (dd, J = 8.2, 2.2, 1H), 8.23 (d, J = 8.5, 1H), 8.08 (d, J =8.3, 2H), 7.65 (s, 2H), 7.52 (dd, J = 19.9, 1.6, 2H), 7.23 (d, J = 8.1,1H), 7.12 (dd, J = 8.2, 1.6, 1H), 1.92 (s, 6H). 68

502(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.42 (s, 1H), 8.18 (d, J = 2.1,2H), 8.15 (d, J = 2.8, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 8.01 (d, J =1.5, 2H), 7.99 (d, J = 1.9, 1H), 7.97 (d, J = 2.0, 1H), 7.81 (s, 1H),7.79 (s, 1H), 1.94 (s, 6H). 69

430(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 11.82 (s, 1H), 9.41 (s, 1H), 8.24-8.13 (m, 2H), 8.04 (d, J = 8.2, 1H), 7.93-7.91 (m, 6H), 7.53 (d, J =12.8, 2H), 6.46 (s, 1H), 1.80 s, 6H). 70

425(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.34 (s, 1H), 8.36 (d, J = 2.2,1H), 8.11 (d, J = 8.5, 1H), 7.99 (dd, J = 8.5, 1.9, 1H), 7.92-7.83 (m,2H), 7.53 (dd, J = 12.2, 5.4, 3H), 7.40 (d, J = 1.8, 1H), 6.76 (s, 2H).71

485(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.46 (s, 1H), 8.26 (dd, J = 7.1,5.0, 3H), 8.23-8.16 (m, 3H), 8.04 (dd, J = 8.5, 1.9, 1H), 7.78 (d, J =2.2, 1H), 7.57 (d, J = 1.8, 1H), 6.83 (s, 2H), 3.35 (s, 3H). 72

436(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.39 (s, 1H), 8.12 (d, J = 8.5,1H), 7.98- 7.93 (m, 3H), 7.89 (d, J = 8.5, 2H), 7.53 (d, J = 1.8, 1H),7.48 (d, J = 1.9, 1H), 7.08 (d, J = 1.8, 1H), 6.07 (s, 2H), 3.81 (s,3H), 1.82 (s, 6H). 73

421(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.49 (d, J = 7.3, 2H), 8.71 (dd, J= 8.2, 2.1, 1H), 8.42 (dd, J = 4.8, 3.2, 2H), 8.19 (d, J = 8.5, 1H),8.06 (dd, J = 8.5, 1.7, 1H), 7.94 (s, 1H), 7.70 (s, 2H), 7.47-7.44 (m,3H). 74

436(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.42 (s, 1H), 8.16 (d, J = 8.4,1H), 7.95- 7.90 (m, 4H), 7.81 (dd, J = 8.5, 1.9, 1H), 7.40 (d, J = 1.9,1H), 7.21 (d, J = 2.3, 1H), 6.96 (d, J = 2.3, 1H), 3.87 (s, 3H), 1.85(s, 6H). 75

450(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.35 (s, 1H), 8.09 (d, J = 8.5,1H), 7.92- 7.88 (m, 3H), 7.87-7.83 (m, 2H), 7.45 (dd, J = 14.5, 1.9,2H), 7.03 (d, J = 2.0, 1H), 5.96 (s, 2H), 4.01 (q, J = 6.5, 2H), 1.79(s, 6H), 1.35 (t, J = 6.9, 3H). 76

451(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.41 (d, J = 1.5, 1H), 8.15 (d, J =8.5, 1H), 8.00 (dd, J = 8.5, 1.8, 1H), 7.88 (q, J = 8.4, 4H), 7.45 (dd,J = 15.9, 1.9, 2H), 7.36 (d, J = 2.0, 1H), 3.84 (s, 3H), 3.80 (s, 3H),1.80 (s, 6H). 77

440(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.37 (s, 1H), 8.09 (d, J = 8.5,1H), 7.97- 7.86 (m, 6H), 7.50 (d, J = 2.2, 1H), 7.45 (d, J = 1.8, 1H),6.62 (s, 2H), 1.81 (s, 6H). 78

462(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.43 (s, 1H), 8.89-8.84 (m, 1H),8.22- 8.17 (m, 3H), 8.11 (s, 1H), 7.97 (d, J = 8.4, 1H), 7.61-7.54 (m,3H), 3.94 (s, 3H), 3.02 (s, 3H), 2.65 (s, 3H).

EXAMPLE 7 Synthesis of Compounds 79-87 Compound 79(S)-1-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one

A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H₂O (30mL) was stirred at r.t overnight. Then the solvents were removed, andthe pH of the residue was adjusted to 2 by using 2N HCl. The resultingmixture was extracted with EtOAc (3×20 mL). The combined organic layerswere dried over Na₂SO₄, and concentrated to give1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield100.0%).

A mixture of 7-bromo-2-hydrazinylquinoxaline (3 g, 12.55 mmol),1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.16 g, 13.81mmol), EDCI (2.89 g, 15.06 mmol), HOBt (2.03 g, 15.06 mmol), and TEA(1.9 g, 18.83 mmol) in DMF (100 mL) was stirred at r.t. overnight. Themixture was diluted with water (10 mL), and extracted with EtOAc (3×100mL). The combined layers were dried over Na₂SO₄, and concentrated invacuo to afford tert-butyl4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylateas pale yellow solid (3.5 g, yield 62%).

A mixture of tert-butyl4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylate(900 mg, 2.0 mmol) in AcOH (10 mL) was refluxed overnight. Then thesolvent was removed, and the residue was purified by ISCO(MeOH/H₂O=20%-90%) to afford8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline as a paleyellow solid (550 mg, yield 83.0%). MS (m/z): 332 (M+H)⁺.

A mixture of 8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline(250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol),HATU (346 mg, 0.90 mmol), and DIEA (116 mg, 0.90 mmol) in DMF (5 mL) wasstirred at r.t. for 6 h. Then the solvents was removed, and the residuewas purified by ISCO (MeOH/H₂O=20%-90%) to afford(S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-oneas pale yellow solid (200 mg, yield 66.0%). MS (m/z): 404 (M+H)⁺.

A mixture of (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one (65 mg, 0.16 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(51 mg, 0.18 mmol), K₂CO₃ (67 mg, 0.48 mmol) and Pd(dppf)Cl₂ (5 mg) indioxane/H₂O (3:1, 4 mL) was microwaved at 150° C. for 0.5 h. Then thesolvents were removed, and the residue was purified by ISCO(MeOH/H₂O=20%-80%) to afford compound 72 as yellow solid (30 mg). ¹HNMR(400 MHz, dmso) δ 9.28 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.32 (s, 1H),8.16-8.12 (m, 2H), 8.05 (dd, J=8.5, 1.5 Hz, 1H), 6.82 (s, 2H), 4.91 (dd,J=7.2, 6.5 Hz, 1H), 4.47 (dd, J=17.8, 11.8 Hz, 2H), 4.29 (t, J=10.6 Hz,1H), 4.15 (t, J=11.2 Hz, 1H), 3.09-2.97 (m, 1H), 2.27 (dd, J=15.6, 14.5Hz, 2H), 1.97 (dd, J=12.0, 4.5 Hz, 1H), 1.78 (dd, J=7.1, 5.0 Hz, 1H),1.25-1.15 (m, 3H). MS (m/z): 486 (M+H)⁺.

The following compounds 80-87 were prepared according to the proceduresfor Compound 79 by using the corresponding intermediates and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art:

Compound Structure LC/MS NMR 80

474(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.27 (s, 1H), 8.33 (s, 1H),8.19-8.08 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.72-7.59 (m, 3H), 7.48 (d,J = 8.3 Hz, 1H), 4.88 (dd, J = 18.5, 12.3 Hz, 1H), 4.42 (dd, J = 24.2,18.1 Hz, 2H), 4.17 (dd, J = 26.5, 14.0 Hz, 2H), 3.06 (d, J = 7.2 Hz,1H), 2.34-2.22 (m, 2H), 2.00 (d, J = 14.6 Hz, 1H), 1.90-1.75 (m, 1H),1.29-1.15 (m, 3H). 81

474(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.27 (s, 1H), 8.33 (s, 1H),8.20-8.12 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.71-7.61 (m, 3H), 7.48 (d,J = 8.4 Hz, 1H), 4.98-4.76 (m, 1H), 4.51-4.37 (m, 2H), 4.25-4.11 (m,2H), 3.12-3.01 (m, 1H), 2.35-2.21 (m, 2H), 2.04-1.94 (dd, J = 33.4, 10.8Hz, 1H), 1.90- 1.77 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H). 82

470(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.26 (s, 1H), 8.72 (d, J = 2.0 Hz,1H), 8.27 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.03 (dd, J = 8.4, 1.5 Hz,1H), 6.82 (s, 2H), 4.33 (d, J = 12.5 Hz, 1H), 3.78 (d, J = 13.3 Hz, 1H),3.57 (d, J = 4.4 Hz, 2H), 3.04-2.96 (m, 1H), 2.60-2.48 (m, 1H),2.38-2.29 (m, 1H), 1.97 (s, 3H), 1.78 (d, J = 12.6 Hz, 2H), 1.43-1.31(m, 1H), 1.28-1.18 (m, 1H). 83

458(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.26 (s, 1H), 8.30 (s, 1H), 8.14(dd, J = 7.5, 5.1 Hz, 2H), 7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.72-7.60 (m,3H), 7.46 (d, J = 8.4 Hz, 1H), 4.38 (d, J = 12.6 Hz, 1H), 3.81 (d, J =14.0 Hz, 1H), 3.54 (d, J = 6.5 Hz, 2H), 3.03 (t, J = 11.8 Hz, 1H),2.60-2.51 (m, 1H), 2.42-2.28 (m, 1H), 1.97 (s, 3H), 1.83 (d, J = 12.8Hz, 2H), 1.40 (dt, J = 10.5, 6.7 Hz, 1H), 1.29-1.20 (m, 1H). 84

444(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.26 (s, 1H), 8.32 (s, 1H),8.19-8.10 (m, 2H), 8.05-8.78 (m, 1H), 7.72-7.58 m, 3H), 7.41 (d, J = 8.1Hz, 1H), 4.38-4.23 (m, 1H), 4.17-4.02 (m, 1H), 3.98- 3.91 (m, 1H),3.88-3.80 (m, 1H), 2.89-2.78 (m, 1H), 2.36-2.23 (m, 2H), 2.15 (s, 3H),1.84 (d, J = 21.4 Hz, 1H), 1.79-1.62 (m, 1H). 85

429(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.22 (d, J = 2.1 Hz, 1H), 8.68 (s,1H), 8.23 (d, J = 3.7 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.01 (d, J =8.5 Hz, 1H), 6.77 (d, J = 6.2 Hz, 2H), 4.67-4.55 (m, 1H), 3.39-3.35 (m,1H), 2.22-2.10 (m, 2H), 2.03-2.93 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.66(m, 2H). 86

428(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.45 (s, 1H), 8.67 (s, 1H), 8.52(s, 1H), 8.18 (d, J = 8.4, Hz, 1H), 8.14 (dd, J = 8.4 Hz, 2.0 Hz, 1H),8.11-8.08 (m, 1H), 6.90 (s, 2H), 3.76-3.61 (m, 4H), 1.99 (m, 2H), 1.92(m, 2H). 87

414(M + H)⁺ ¹H NMR (400 MHz, cd3od) δ 9.23 (s, 1H), 8.99 (d, J = 1.9 Hz,1H), 8.61 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.14 (d, J =1.9 Hz, 1H), 7.97 (dd, J = 8.5, 1.9 Hz, 1H), 4.47 (m 2H), 4.38 (m 2H),2.73 (m, 4H), 1.88 (m, 4H).

EXAMPLE 8 Synthesis of Compounds 88-118 Compound 88(4-(8-(6-amino-5-(trifluoromethyl)pyridine-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanone

A mixture of 2,8-dichloro-7-nitro-1,5-naphthyridine (3.55 g, 14.55 mmol)and K₂CO₃ (6.02 g, 43.65 mmol) in DMF (8 mL) was stirred at r.t.overnight, and then poured into ice-water (˜20 mL). The precipitate wascollected, washed with water three times, and dried in vacuo to affordtert-butyl4-(6-chloro-3-nitro-1,5-naphthyridin-4-ylamino)piperidine-1-carboxylateas yellow solid (5.22 g, yield 88%) which was used in next step withoutfurther purification. MS (m/z): 409 (M+H)⁺.

A mixture of tert-butyl 4-(6-chloro-3-nitro-1,5-naphthyridin-4-ylamino)piperidine-1-carboxylate (600 mg, 1.47 mmol) and SnCl₂.H₂O (996 mg, 4.41mmol) in ethyl acetate (20 mL) was stirred at r.t. for 2 h, and was thenalkalized with 5% NaOH solution. The mixture was filtered through a padof celite. The filtrate was extracted with ethyl acetate (3×15 mL). Theorganic layers were combined and washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated to give tert-butyl4-(3-amino-6-chloro-1,5-naphthyridin-4-ylamino) piperidine-1-carboxylateas a yellow solid (499 mg, yield 90%) which was used in the next stepwithout further purification. MS (m/z): 378 (M+H)⁺.

A mixture of tert-butyl4-(3-amino-6-chloro-1,5-naphthyridin-4-ylamino)piperidine-1-carboxylate(200 mg, 0.53 mmol), triethyl orthoformate (94 mg, 0.64 mmol), and PyHCl(6 mg, 0.053 mmol) in Toluene (5 mL) was refluxed for 3.5 h. The solventwas removed under vacuum and the residue was added to a solution of HClin MeOH (6N, 3 mL). The reaction mixture was stirred at r.t. for 3 h,and was then concentrated under vacuum. The residue was dissolved indichloromethane (20 mL). the resulting solution was washed withsaturated NaHCO₃ (10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated to to give8-chloro-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthayridine as ayellow solid (110 mg, yield 72%) which was used in next step withoutfurther purification.

To a solution of8-chloro-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthayridine (110mg, 0.382 mmol) and Et₃N (106 μL, 0.764 mmol) in THF (15 mL) was addedcyclopropanecarbonyl chloride (38 μL, 0.420 mmol) while cooling with anice-water bath. The reaction mixture was stirred at r.t. for 3 h, andwas then concentrated under vacuum. The residue was dissolved in ethylacetate (20 mL). The resulting solution was washed with saturated NaHCO₃(10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give(4-(8-chloro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanoneas a yellow solid (100 mg, yield 73%) which was used in the next stepwithout further purification. MS (m/z): 356 (M+H)⁺.

A mixture of(4-(8-chloro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanone(100 mg, 0.281 mmol), PdCl₂(dppf)₂ (12 mg, 0.014 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine-2-amine(97 mg, 0.337 mmol), and 2 N K₂CO₃ solution (1 mL) in dioxane (4 mL) wasmicrowaved at 150° C. for 30 min. The solvent was removed and theresidue was purified by ISCO (MeOH/H₂O 0%˜100%) to give compound 88 as ayellowish solid (70 mg). ¹H NMR (400 MHz, dmso) δ 9.20 (s, 1H), 9.13 (d,J=1.9, 1H), 8.71 (s, 1H), 8.59 (d, J=2.0, 1H), 8.49 (d, J=8.9, 1H), 8.32(d, J=8.9, 1H), 6.99 (s, 2H), 5.98-5.92 (m, 1H), 4.66 (s, 1H), 4.58 (s,1H), 3.25 (s, 2H), 2.35 (s, 2H), 2.09-2.01 (m, 2H), 2.01-1.90 (m, 1H),0.80-0.71 (m, 4H). MS (m/z): 482 (M+H)⁺.

The following compounds 89-118 were prepared according to the proceduresfor Compound 88 by using the corresponding intermediates and boronicacid or ester under appropriate conditions that could be recognized byone skilled in the art.

Compound Structure LC/MS NMR 89

475(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.38 (s, 1H), 9.08 (d, J = 2.6 Hz,1H), 8.79 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 8.9 Hz, 1H),8.47 (dd, J = 8.4, 2.5 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.16 (d, J =2.1 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 6.90 (s, 2H), 1.85 (s, 6H). 90

421(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.32 (d, J = 1.2 Hz, 1H), 9.11 (s,1H), 8.77 (d, J = 1.2 Hz, 1H), 8.49-8.43 (m, 2H), 8.37 (s, 1H), 8.22 (d,J = 9.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 6.20 (s, 2H),2.10 (s, 3H), 1.87 (s, 6H). 91

406(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.41 (s, 1H), 9.11 (d, J = 2.0 Hz,1H), 8.87 (s, 1H), 8.82 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.39 (t, J =7.5 Hz, 2H), 8.05 (d, J = 6.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.28(d, J = 8.2 Hz, 1H), 2.49 (s, 3H), 1.89 (s, 6H). 92

452(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.40 (s, 1H), 9.12 (d, J = 2.5 Hz,1H), 8.81 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.40- 8.35 (m, 2H),7.97-7.92 (m, 2H), 7.80 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H),1.90 (s, 6H). 93

442(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.45 (s, 1H), 9.16 (s, 1H), 9.10 (s,1H), 8.96 (s, 1H), 8.86 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.55 (d, J =8.8 Hz, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.08-7.98 (m, 3H), 7.82 (t, J =7.5 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 1.93 (s, 6H). 94

408(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.36 (s, 1H), 9.10 (s, 1H), 8.80 (s,1H), 8.64 (s, 2H), 8.52 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H),8.25 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.07 (s, 2H), 1.91(s, 6H). 95

437(M + H)⁺ 1HNMR (400 MHz, dmso) δ 9.34 (s, 1H), 9.13 (d, J = 2.4 Hz,1H), 8.76 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.44- 8.38 (m, 1H), 8.26(d, J = 9.0 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 8.4 Hz,1H), 6.18 (s, 2H), 3.83 (s, 3H), 1.86 (s, 6H). 96

470(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.37 (s, 1H), 9.04 (d, J = 1.3 Hz,1H), 8.61 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H),8.06 (d, J = 8.8 Hz, 1H), 6.17-5.98 (m, 1H), 5.32 (m, 2H), 5.00 (m, 1H),4.13 (s, 1H), 3.35 (m, 1H), 2.83 (s, 1H), 2.57 (m, 2H), 2.46 (m, 2H),2.03 (m, 4H), 1.32-1.31 (m, 3H). 97

541(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.31 (s, 1H), 9.22 (s, 1H), 8.85(s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.9, 1H), 8.44 (d, J = 8.9, 1H),7.11 (s, 2H), 3.69 (m, 4H), 3.63 (m, 3H), 3.51 (m, 3H), 3.31 (m, 2H),3.16 (m, 2H), 2.39-2.25 (m, 5H). 98

499(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.31 (s, 1H), 9.22 (s, 1H), 8.84(s, 1H), 8.72 (s, 1H), 8.60 (d, J = 8.9, 1H), 8.43 (d, J = 8.9, 1H),7.11 (s, 2H), 3.27 (s, 2H), 3.18 (m, 2H), 3.14 (s, 3H), 2.89 (s, 3H),2.40-2.18 (m, 7H). 99

476(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.36 (s, 1H), 8.60 (d, J = 8.8 Hz,1H), 8.50 (m 1H), 8.31 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.83 (m, 1H),6.06- 5.77 (m, 1H), 4.10 (d, 6H), 3.25 (m, 2H), 3.09 (s, 3H), 2.98 (s,3H), 2.74-2.60 (m, 2H), 2.45 (m, 2H), 2.31-2.20 (m, 4H). 100

430(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.35 (s, 1H), 9.29 (d, J = 2.0 Hz,1H), 8.59 (d, J = 8.8 Hz, 1H), 8.33 (m, 1H), 8.27 (s, 1H), 8.07 (d, J =8.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 5.91-5.71 (m, 1H), 3.34 (m, 2H),3.23 (m, 2H), 3.10 (s 3H), 2.98 (s 3H), 2.67 (s 3H), 2.54 (m, 2H), 2.45(m, 2H), 2.26 (m, 2H). 101

485(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.21 (s, 1H), 9.15 (s, 1H), 8.73(s, 1H), 8.61 (s, 1H), 8.50 (d, J = 8.8, 1H), 8.34 (d, J = 8.8, 1H),7.01 (s, 2H), 6.63 (s, 1H), 5.87 (s, 1H), 4.26 (m, 2H), 3.07 (m, 2H),2.84 (m, 2H), 2.26 (m, 2H), 1.99 (m, 2H), 1.02 (m, 3H). 102

456(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.25 (s, 1H), 9.17 (s, 1H), 8.73(s, 1H), 8.64 (s, 1H), 8.54 (d, J = 8.7, 1H), 8.37 (d, J = 8.9, 1H),7.04 (s, 2H), 5.98 (s, 1H), 4.72 (m, 1H), 4.15 (m, 1H), 3.24 (m, 1H),2.73 (m, 1H), 2.34 (m, 2H), 2.11 (s, 3H), 2.00 (m, 2H). 103

492(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.26 (s, 1H), 9.14 (d, J = 1.9,1H), 8.79 (s, 1H), 8.63 (d, J = 2.1, 1H), 8.55 (d, J = 8.9, 1H), 8.37(d, J = 8.9, 1H), 7.04 (s, 2H), 5.84 (m, 1H), 3.90 (m, 2H), 2.98 (s,3H), 2.46 (m, 2H), 2.29-2.19 (m, 2H), 2.08-1.88 (m, 2H). 104

474(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.44-9.29 (m, 1H), 8.71 (dd, J =7.7, 5.4, 2H), 8.59- 8.50 (m, 1H), 8.32 (d, J = 8.9, 1H), 8.18 (s, 1H),7.90 (d, J = 5.9, 2H), 7.84-7.74 (m, 2H), 6.89 (s, 2H), 1.83 (s, 6H).105

498(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.25 (d, J = 5.7, 1H), 9.16 (s,1H), 8.78-8.76 (m, 1H), 8.70-8.67 (m, 1H), 8.53 (d, J = 8.8, 1H), 8.37(d, J = 8.9, 1H), 7.06 (s, 2H), 5.77-5.73 (m, 1H), 4.40 (d, J = 5.4,2H), 4.24 (d, J = 5.6, 2H), 2.86-2.83 (m, 2H), 2.61 (s, 2H), 2.29-2.13(m, 6H), 1.37 (s, 3H). 106

415(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.27 (d, J = 12.4, 1H), 9.20 (d, J= 10.7, 1H), 8.79 (d, J = 12.4, 1H), 8.66 (d, J = 10.7, 1H), 8.60-8.50(m, 1H), 8.39 (t, J = 10.6, 1H), 7.06 (d, J = 11.0, 2H), 5.97-5.93 (m,1H), 4.17-4.12 (m, 2H), 3.61-3.55 (m, 2H), 2.31- 2.23 (m, 4H). 107

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.25 (d, J = 4.2, 1H), 9.18 (s,1H), 8.74 (s, 1H), 8.64 (s, 1H), 8.54 (dd, J = 8.5, 3.5, 1H), 8.42-8.34(m, 1H), 7.05 (s, 2H), 6.00-5.95 (m, 1H), 4.74-4.71 (m, 1H), 4.56-4.54(m, 1H), 4.39- 4.36 (m, 1H), 3.22-3.18 (m, 1H), 2.82-2.79 (m, 1H),2.41-2.38 (m, 2H), 2.17- 1.98 (m, 2H), 1.27-1.25 (m, 3H). 108

451(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.30 (d, J = 1.4 Hz, 1H), 9.08 (d, J= 2.5 Hz, 1H), 8.73 (d, J = 1.3 Hz, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.36(dd, J = 8.4, 2.6 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 1.8Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 6.07 (s, 2H), 4.05 (q,J = 6.9 Hz, 2H), 1.81 (s, 6H), 1.35 (t, J = 6.9 Hz, 3H). 109

444(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.19 (s, 1H), 9.14 (s, 1H), 8.57(s, 1H), 8.49 (d, J = 7.7, 3H), 8.31 (d, J = 7.7, 1H), 6.95 (s, 2H),5.01 (d, J = 6.2, 2H), 3.41 (t, J = 7.0, 4H), 2.88 (t, J = 7.0, 2H),2.39 (m 4H). 110

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.26 (s, 1H), 9.18 (s, 1H), 8.74(s, 1H), 8.64 (s, 1H), 8.55 (d, J = 8.9, 1H), 8.38 (d, J = 8.9, 1H),7.04 (s, 2H), 6.05-5.92 (m, 1H), 4.73- 4.70 (m, 1H), 4.55-4.52 (m, 1H),4.38-4.35 (m, 1H), 3.24-3.21 (m, 1H), 2.83- 2.77 (m, 1H), 2.40-2.37 (m,2H), 2.15-1.97 (m, 2H), 1.28-1.22 (m, 3H). 111

428(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.24 (s, 1H), 9.18 (d, J = 2.0,1H), 8.64 (d, J = 2.1, 1H), 8.56-8.51 (m, 2H), 8.37 (d, J = 8.9, 1H),7.01 (s, 2H), 5.04 (t, J = 6.3, 2H), 3.07 (t, J = 6.3, 3H), 2.51 (d, J =1.7, 4H), 1.65 (s, 4H). 112

438(M + H)⁺ ¹HNMR (400 MHz, dmso) δ 9.32 (s, 1H), 8.77 (s, 1H), 8.57 (d,J = 8.7 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.07 (dd, J = 4.9, 1.9 Hz,1H), 7.78 (dd, J = 7.5, 1.9 Hz, 1H), 6.64 (dd, J = 7.5, 4.9 Hz, 1H),6.57 (s, 2H), 5.85-5.77 (m, 1H), 4.75- 4.67 (m, 1H), 4.62-4.54 (m, 1H),2.93-2.76 (m, 1H), 2.42-2.28 (m, 2H), 2.18- 1.96 (m, 4H), 0.81-0.72 (m,4H). 113

417(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.38 (d, J = 1.9, 1H), 9.32 (s,1H), 8.75 (s, 1H), 8.64 (d, J = 8.8, 1H), 8.54 (dd, J = 8.1, 2.3, 1H),8.42 (d, J = 8.8, 1H), 7.52 (d, J = 7.9, 1H), 5.89-5.84 (m, 1H), 4.78-4.64 (m, 1H), 4.61-4.47 (m, 1H), 4.42-4.26 (m, 1H), 3.31-3.27 (m, 1H),2.94- 2.82 (m, 1H), 2.58 (s, 3H), 2.45-2.34 (m, 2H), 2.22- 2.03 (m, 2H),1.28-1.24 (m, 3H). 114

458(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.18 (s, 1H), 9.11 (s, 1H), 8.58(s, 1H), 8.51-8.39 (m, 2H), 8.29 (d, J = 8.9 Hz, 1H), 6.97 (s, 2H), 4.88(t, J = 6.7 Hz, 2H), 3.39 (d, J = 4.2 Hz, 4H), 2.20 (tt, J = 13.7, 6.9Hz, 8H). 115

472(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.22 (s, 1H), 9.13 (s, 1H), 8.74(s, 1H), 8.63 (s, 1H), 8.51 (d, J = 8.9 Hz, 1H), 8.34 (d, J = 8.9 Hz,1H), 7.00 (s, 2H), 5.71 (m, 1H), 3.47 (m, 3H), 3.10 (m, 2H), 2.41 (m,2H), 2.24 (m, 2H), 2.13 (m, 5H), 1.67-1.57 (m, 2H). 116

458(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.22 (s, 1H), 9.15 (d, J = 2.0 Hz,1H), 8.73 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 8.9 Hz, 1H),8.35 (d, J = 8.9 Hz, 1H), 7.00 (s, 2H), 5.69 (s, 1H), 4.61-4.34 (m, 1H),3.54 (s, 2H), 3.12 (d, J = 14.3 Hz, 4H), 2.20 (d, J = 7.9 Hz, 6H). 117

468(M + H)⁺ 1HNMR (400 MHz, dmso) δ 9.30-9.09 (m, 2H), 8.84- 8.44 (m,4H), 8.37 (s, 1H), 7.01 (s, 2H), 6.93-6.82 (m, 1H), 6.27-6.09 (m, 1H),6.07-5.90 (m, 1H), 5.81- 5.62 (m, 1H), 4.81-4.67 (m, 1H), 4.49-4.32 (m,1H), 2.86-2.75 (m, 1H), 2.42- 2.24 (m, 3H), 2.15-1.97 (m, 2H). 118

480(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.26 (d, J = 2.7, 1H), 9.18 (d, J =2.1, 1H), 8.74 (d, J = 5.9, 1H), 8.64 (d, J = 2.1, 1H), 8.55 (d, J =8.9, 1H), 8.38 (d, J = 8.9, 1H), 7.04 (s, 2H), 6.08-5.96 (m, 1H),4.67-4.58 (m, 2H), 2.92-2.83 (m, 1H), 2.47-2.34 (m, 3H), 2.21-2.11 (m,1H), 2.06 (s, 3H), 2.03-1.97 (m, 1H).

EXAMPLE 9 Synthesis of Compound 119-146 Compound 119(4-(8-(6-amino-5-(trifluoromethyl)pyridine-3yl)-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanone

A mixture of tert-butyl 4-(3amino-6-chloro-1,5-naphthyridin-4-ylamino)piperidine-1-carboxylate (200 mg, 0.53 mmol) in acetic acid (3 mL) wasstirred at 100° C. overnight. The solvent was removed under vacuum andthe residue was added to a solution of HCl in MeOH (6N, 3 mL). Thereaction mixture was stirred at r.t. for 2 h, and was then concentratedunder vacuum. The residue was dissolved in dichloromethane (20 mL). Theresulting solution was washed with saturated NaHCO₃ (10 mL) and brine(10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to givecrude8-chloro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridineas a yellow solid (110 mg, yield 68%) which was used in the next stepwithout further purification.

To a solution of8-chloro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridine(110 mg, 0.364 mmol) and Et₃N (101 μL, 0.728 mmol) in THF (15 mL) wasadded cyclopropanecarbonyl chloride (36 μL, 0.401 mmol) while coolingwith an ice-water bath. The reaction mixture was stirred at r.t. for 3h, and was then concentrated under vacuum. The residue was dissolved ina mixture of CH₂Cl₂ (10 mL) and H₂O (10 mL). The resulting solution wasthen extracted with EA (2×10 mL). The combined organic layers wereconcentrated to give crude(4-(8-chloro-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanone as a yellow solid (105 mg, yield80%) which was used in the next step without further purification. MS(m/z): 370 (M+H)⁺.

A mixture of crude(4-(8-chloro-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)(cyclopropyl)methanone (105 mg, 0.284 mmol), PdCl₂(dppf)₂(12 mg, 0.014 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine-2-amine (98 mg, 0.340 mmol), and 2 N K₂CO₃ solution (1 mL) indioxane (4 mL) was microwaved at 150° C. for 30 min. The solvent wasremoved and the residue was purified by ISCO (MeOH/H2O 0%˜100%) toobtain compound 119 as a yellowish solid (57 mg). ¹H NMR (400 MHz, dmso)δ 9.11 (d, J=6.8, 2H), 8.58 (s, 1H), 8.48 (d, J=8.8, 1H), 8.29 (d,J=8.3, 1H), 6.97 (s, 2H), 4.67-4.58 (m, 2H), 4.06 (s, 1H), 2.75 (m, 5H),2.11-2.04 (m, 4H), 0.81 (s, 1H), 0.71 (m, 4H). MS (m/z): 496 (M+H)⁺.

The following compounds 120-146 were prepared according to theprocedures for Compound 119 by using the corresponding intermediates andboronic acid or ester under appropriate conditions that could berecognized by one skilled in the art.

Compound Structure LC/MS NMR 120

484(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.24 (s, 1H), 9.03 (s, 1H), 8.57(d, J = 8.7 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 5.25 (s,3H), 5.11-4.92 (m, 1H), 4.16 (m, 1H), 3.28 (m, 2H), 2.78 (m, 5H), 2.45(m, 3H), 2.20 (m, 3H), 1.24 (m, 4H). 121

512(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.39-9.11 (m, 2H), 8.62 (s, 1H),8.51 (t, J = 8.5, 1H), 8.31 (d, J = 8.3, 1H), 7.02 (s, 2H), 6.82-6.36(m, 1H), 4.39-4.37 (m, 2H), 4.26-4.23 (m, 2H), 2.84-2.79 (m, 5H), 2.64-2.61 (m, 2H), 2.27-2.19 (m, 3H), 2.09-1.98 (m, 3H), 1.35 (s, 3H). 122

500(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.14 (d, J = 3.9, 1H), 8.66-8.62(m, 1H), 8.52 (dd, J = 8.8, 3.3, 1H), 8.37- 8.33 (m, 1H), 8.21-8.18 (m,1H), 7.01 (s, 2H), 5.36- 4.93 (m, 1H), 4.75-4.72 (m, 1H), 4.58-4.55 (m,1H), 4.47-4.32 (m, 1H), 3.19-3.16 (m, 2H), 2.79 (s, 3H), 2.21-1.91 (m,4H), 1.28-1.24 (m, 3H). 123

513(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.19 (s, 1H), 9.13 (s, 1H), 8.62(s, 1H), 8.51 (d, J = 8.9, 1H), 8.32 (d, J = 8.8, 1H), 7.01 (s, 2H),3.24 (s, 2H), 3.12 (m, 3H), 2.83 (m, 6H), 2.32 (m, 2H), 2.01 (s, 3H),1.23 (s, 3H). 124

555(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.15 (d, J = 22.8, 2H), 8.61 (s,1H), 8.49 (d, J = 8.0, 1H), 8.31 (d, J = 8.3, 1H), 7.04 (s, 2H), 4.12(s, 1H), 3.65-3.44 (m, 8H), 3.26-3.03 (m, 7H), 2.81 (s 3H), 2.30 (m,2H), 2.02 (m, 2H). 125

539(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.19 (s, 1H), 9.13 (s, 1H), 8.63(s, 1H), 8.51 (d, J = 8.9, 1H), 8.32 (d, J = 8.9, 1H), 7.01 (s, 2H),3.51 (m, 2H), 3.23-3.09 (m, 8H), 2.82 (s 3H), 2.34 (m, 2H), 2.05-1.72(m, 7H). 126

500(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.18-9.14 (m, 1H), 8.64- 8.59 (m,1H), 8.52 (d, J = 8.8, 1H), 8.34 (d, J = 7.8, 1H), 8.26-8.23 (m, 1H),7.00 (s, 2H), 5.44-4.86 (m, 1H), 4.74-4.70 (m, 1H), 4.58-4.55 (m, 1H),4.50-4.28 (m, 1H), 3.21- 3.16 (m, 2H), 2.79 (s, 3H), 2.21-2.06 (m, 3H),2.04- 1.92 (m, 1H), 1.28-1.23 (m, 3H). 127

431(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.32 (s, 1H), 9.21 (s, 1H), 8.60(d, J = 8.8, 1H), 8.55- 8.49 (m, 1H), 8.38 (d, J = 6.9, 1H), 7.52 (d, J= 7.7, 1H), 4.73-4.68 (m, 2H), 4.52-4.33 (m, 2H), 2.96- 2.80 (m, 5H),2.59-2.53 (m, 5H), 2.06-1.88 (m, 2H), 1.29-1.21 (m, 3H). 128

519(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.10 (s, 1H), 8.59 (s, 1H), 8.47(d, J = 8.8 Hz, 2H), 8.27 (d, J = 8.8 Hz, 1H), 7.86-7.63 (m, 1H), 7.53(d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 6.99 (m, 2H), 3.69 (m, 2H), 3.12 (m,4H), 2.80 (s, 3H), 2.13 (m, 5H). 129

472(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.13 (s, 1H), 8.63 (s, 1H), 8.51(d, J = 8.9 Hz, 1H), 8.42 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 4.33-4.13(m, 1H), 3.62 (s, 6H), 3.14 (s, 3H), 2.81 (s, 4H), 2.27 (s, 3H), 2.00(m, 3H). 130

486(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.09 (s, 1H), 8.57 (s, 1H), 8.45(d, J = 8.8 Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 8.9 Hz, 1H), 6.97 (s,2H), 3.75 (s, 6H), 3.52 (s, 3H), 3.26 (s, 3H), 3.11 (d, J = 10.1 Hz,3H), 2.78 (s, 3H), 2.57 (t, J = 5.9 Hz, 2H), 2.24 (d, J = 10.0 Hz, 3H).131

443(M + H)⁺ ¹H NMR (400 MHz, cdcl 3) δ 9.32 (d, J = 1.4, 1H), 8.64-8.48(m, 2H), 8.01 (dd, J = 8.8, 1.5, 1H), 7.27 (d, J = 0.9, 1H), 5.47 (s,2H), 4.31 (d, J = 8.3, 2H), 3.71 (t, J = 11.6, 2H), 3.17 (d, J = 7.3,2H), 1.65 (m 4H), 1.58 (t, J = 7.4, 3H). 132

533(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.11 (m, 2H), 8.59 (m, 2H), 8.48(d, J = 8.9 Hz, 1H), 8.36-8.22 (m, 1H), 8.01-7.87 (m, 1H), 7.72- 7.63(m, 1H), 7.54-7.41 (m, 1H), 7.01 (s, 2H), 4.92- 4.76 (m, 1H), 4.05-3.92(m, 1H), 3.26-3.19 (m, 1H), 3.11-2.88 (m, 2H), 2.78 (s, 3H), 2.43-1.83(m, 4H). 133

429(M + H)⁺ ¹H NMR (400 MHz, cd 3 od) δ 9.24 (s, 1H), 9.09 (s, 1H), 8.67(s, 1H), 8.53 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 9.2 Hz, 1H), 4.26-4.17(m, 2H), 3.77-3.70 (m, 2H), 2.87 (s, 3H), 2.17- 1.73 (m, 4H) 134

386(M + H)⁺ ¹H NMR (400 MHz, dmso- d6) δ 9.64 (s, 1H), 9.42 (s, 1H),8.21 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.26(s, 1H), 4.25-4.14 (m, 2H), 3.78-3.67 (m, 2H), 2.85 (s, 3H), 2.02-1.76(m, 4H) 135

385(M + H)⁺ ¹H NMR (400 MHz, dmso- d6) δ 11.81 (s, 1H), 9.27 (s, 1H),9.13 (s, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.53(d, J = 3.2 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 4.18-4.10 (m, 2H),3.70-3.62 (m, 2H), 2.79 (s, 3H), 2.01- 1.70 (m, 4H) 136

458(M + H)⁺ ¹H NMR (400 MHz, cdcl 3) δ 9.20 (s, 1H), 8.81 (d, J = 2.1,1H), 8.50 (d, J = 8.8, 1H), 8.15 (s, 1H), 7.98 (d, J = 8.8, 1H), 7.10-6.96 (m, 1H), 4.71 (s, 2H), 3.81 (m, 4H), 2.95 (s, 3H), 2.52 (m, 6H),2.40 (s, 1H), 2.30 (m, 2H), 2.28 (s, 3H), 1.92 (m, 2H), 1.70 (m, 2H) 137

512(M + H)⁺ ¹H NMR (400 MHz, cdcl 3) δ 9.23 (s, 1H), 9.02 (d, J = 1.7,1H), 8.66 (d, J = 1.9, 1H), 8.56 (d, J = 8.8, 1H), 8.01 (d, J = 8.8,1H), 7.00-6.86 (m, 1H), 5.25 (s, 2H), 3.80 (m, 4H), 3.49 (m, 1H), 2.97(s, 3H), 2.56 (m, 3H), 2.48 (m, 2H), 2.40 (s, 1H), 2.28 (m, 2H), 1.90(m, 2H), 1.68 (m, 2H) 138

506(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.19 (s, 1H), 9.15 (s, 1H),8.65-8.48 (m, 2H), 8.32 (d, J = 8.8, 1H), 7.00 (s, 2H), 3.92-3.89 (m,2H), 3.06 (s, 3H), 2.94 (d, J = 11.2, 2H), 2.82 (s, 3H), 2.50 (s, 3H),2.18 (s, 2H). 139

454(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.54 (s, 2H), 9.21 (s, 1H), 8.62(d, J = 8.8, 1H), 8.38 (d, J = 8.8, 1H), 4.92- 4.56 (m, 1H), 4.02 (s,3H), 3.85 (d, J = 11.5, 2H), 3.17 (s, 3H), 3.03 (d, J = 11.6, 2H), 2.82(s, 3H), 2.53- 2.51 (m, 2H), 2.29-1.81 (m, 2H). 140

482(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.23-9.08 (m, 2H), 8.52 (d, J =8.8, 1H), 8.33 (d, J = 8.7, 1H), 7.03-6.86 (m, 3H), 6.16 (d, J = 16.7,1H), 5.78-5.68 (m, 1H), 4.78-4.75 (m, 1H), 4.42- 4.36 (m, 1H), 3.32-3.19(m, 4H), 2.86-2.79 (m, 1H), 2.78 (s, 3H), 2.22- 2.06 (m, 3H). 141

428(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.06 (s, 1H), 8.73 (s, 1H), 8.41(d, J = 8.9, 1H), 8.28- 8.25 (m, 2H), 8.17-7.97 (m, 2H), 6.95-6.80 (m,1H), 6.25-6.06 (m, 2H), 5.73-5.66 (m, 1H), 4.83- 4.68 (m, 1H), 4.61-4.45(m, 1H), 4.42-4.28 (m, 1H), 3.53 (s, 3H), 3.28- 3.19 (m, 2H), 2.95-2.86(m, 1H), 2.74 (s, 3H), 2.13-2.07 (m, 3H). 142

472(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.18 (s, 1H), 9.11 (s, 1H), 8.58(s, 1H), 8.51-8.39 (m, 2H), 8.29 (d, J = 8.9 Hz, 1H), 6.97 (s, 2H), 4.88(t, J = 6.7 Hz, 2H), 3.39 (d, J = 4.2 Hz, 4H), 2.20 (m, 8H). 143

511(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.25 (s, 1H), 9.15 (s, 1H), 8.82(s, 1H), 8.56 (d, J = 8.8, 1H), 8.38 (s, 1H), 4.57 (d, J = 39.0, 2H),4.06 (s, 4H), 2.76 (s, 5H), 2.01 (s, 4H), 0.79 (d, J = 6.9, 1H), 0.68(s, 4H). 144

494(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.14 (s, 2H), 8.61 (s, 1H), 8.52(d, J = 8.8, 1H), 8.33 (d, J = 8.8, 1H), 7.01 (s, 2H), 4.69-4.56 (m,2H), 3.35-3.26 (m, 3H), 2.88- 2.83 (m, 1H), 2.79 (s, 3H), 2.28-2.13 (m,3H), 2.06 (s, 3H). 145

496(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.13 (s, 2H), 8.60 (s, 1H), 8.51(d, J = 8.8, 1H), 8.32 (d, J = 8.7, 1H), 7.00 (s, 2H), 6.75 (td, J =13.4, 6.6, 1H), 6.61 (d, J = 15.2, 1H), 4.81-4.68 (m, 1H), 4.46- 4.22(m, 1H), 3.81-3.72 (m, 1H), 3.28-3.18 (m, 2H), 2.80-2.78 (m, 1H), 2.77(s, 3H), 2.22-2.02 (m, 3H), 1.87 (d, J = 6.7, 3H) 146

498(M + H)⁺ ¹H NMR (400 MHz, cdcl3) δ 9.48 (s, 1H), 9.30 (s, 1H),8.67-8.44 (m, 2H), 8.01 (s, 1H), 5.64 (s, 2H), 4.30- 4.29 (d, 2H), 4.11(s, 2H), 3.71-3.65 (m, 3H), 2.63 (m, 4H), 1.81 (m, 4H), 1.68 (m, 4H).

EXAMPLE 10 Synthesis of Compounds 147-178 Compound 1472,4-difluoro-N-(2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)pyridin-3-yl)benzenesulfonamide

A mixture of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.84 mmol) andAcOH (5 mL) was refluxed overnight. After cooling to r.t., the mixturewas treated with water (10 mL); the solid was collected on a filter anddried by vacuum to give8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as gray solid (200mg, yield: 91.0%).

A mixture of 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (60 mg,0.23 mmol),2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)benzenesulfonamide(107 mg, 0.25 mmol), K₂CO₃ (95 mg, 0.69 mmol) and Pd(dppf)Cl₂ (6 mg) indioxane/H₂O (3:1, 4 mL) was microwaved at 160° C. for 0.5 h. Then thesolvent was removed, and the residue was purified by ISCO(MeOH/H₂O=20%-80%) to give compound 147 as white solid (60 mg). ¹HNMR(400 MHz, dmso) δ 10.44 (s, 1H), 9.26 (s, 1H), 8.47 (d, J=1.7 Hz, 1H),8.34 (d, J=1.5 Hz, 1H), 8.13 (t, J=10.3 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H),7.92 (dd, J=8.4, 1.5 Hz, 1H), 7.76 (dd, J=14.9, 8.5 Hz, 1H), 7.51 (dd,J=14.2, 5.4 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 3.68 (s, 3H), 3.17 (s, 3H).MS (m/z): 483 (M+H)⁺.

The following compounds 148-178 were prepared according to theprocedures for Compound 147 by using the corresponding intermediates andboronic acid or ester under appropriate conditions that could berecognized by one skilled in the art.

Compounds Structure LC/MS NMR 148

499(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.39 (s, 1H), 8.82 (s, 2H), 8.30(s, 1H), 7.92 (d, J = 8.4, 1H), 7.86 (d, J = 2.2, 1H), 7.82 (d, J = 6.4,1H), 7.78 (dd, J = 8.4, 1.9, 1H), 7.51 (t, J = 8.8, 1H), 7.21 (t, J =8.6, 1H), 3.69 (s, 3H), 3.62 (s, 3H). 149

513(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.38 (s, 1H), 8.83-8.77 (m, 2H),8.32 (d, J = 2.2, 1H), 7.90 (d, J = 8.4, 1H), 7.86 (d, J = 2.3, 1H),7.84-7.79 (m, 1H), 7.78-7.74 (m, 1H), 7.56-7.49 (m, 1H), 7.23-7.18 (m,2.2, 1H), 3.99 (q, J = 7.2, 2H), 3.69 (s, 3H), 1.34 (t, J = 7.2, 3H).150

385(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.30 (s, 1H), 8.52 (d, J = 2.3,1H), 8.43 (d, J = 1.7, 1H), 8.19 (d, J = 8.4, 1H), 8.07 (d, J = 2.3,1H), 8.00 (dd, J = 8.4, 1.8, 1H), 4.00 (s, 3H), 3.22 (s, 3H), 3.10 (s,3H). 151

497(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.15 (s, 1H), 8.82 (s, 1H), 8.54(d, J = 3.5, 1H), 8.52 (s, 1H), 8.28 (d, J = 8.9, 1H), 8.14 (s, 1H),7.84-7.76 (m, 1H), 7.53 (t, J = 8.7, 1H), 7.20 (td, J = 8.6, 2.2, 1H),4.45 (s, 3H), 3.78 (s, 3H), 2.69 (s, 3H). 152

465(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.45 (s, 1H), 8.21 (d, J = 8.4,1H), 8.03 (d, J = 2.3, 1H), 7.99-7.90 (m, 3H), 7.66 (d, J = 2.3, 1H),7.62 (d, J = 1.9, 1H), 7.59-7.53 (m, 2H), 3.96 (s, 3H), 3.02 (s, 3H).153

483(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.41 (s, 1H), 9.27 (s, 1H), 8.92(d, J = 2.0, 1H), 8.60-8.56 (m, 2H), 8.51 (s, 1H), 8.35 (d, J = 8.9,1H), 7.79 (td, J = 8.6, 6.4, 1H), 7.61-7.52 (m, 1H), 7.21 (td, J = 8.4,2.1, 1H), 4.47 (s, 3H), 3.77 (s, 3H). 154

484(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 8.54 (d, J = 8.1,1H), 8.28-8.21 (m, 4H), 7.79 (d, J = 7.0, 1H), 7.21- 7.18 (m, 1H),7.03-6.99 (m, 1H), 4.73 (s, 3H), 3.83 (s, 3H). 155

439(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.31 (s, 1H), 8.64 (d, J = 2.0,1H), 8.44 (d, J = 1.7, 1H), 8.18 (dd, J = 11.1, 5.4, 2H), 8.01 (dd, J =8.4, 1.8, 1H), 4.00 (s, 3H), 3.23 (s, 3H). 156

467(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.31 (s, 1H), 8.62 (s, 1H), 8.35(d, J = 1.6, 1H), 8.19 (d, J = 8.4, 1H), 8.14 (s, 1H), 7.95-7.76 (m,3H), 7.51-7.47 (m, 1H), 7.22-7.19 (m, 1H), 3.16 (s, 3H), 2.36 (s, 3H).157

499(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.12 (s, 1H), 8.45 (d, J = 1.9,1H), 8.34 (d, J = 2.1, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.4, 1H), 7.94(d, J = 2.3, 1H), 7.88 (dd, J = 8.4, 2.0, 1H), 7.82-7.77 (m, 1H),7.56-7.48 (m, 1H), 7.21 (td, J = 8.2, 2.2, 1H), 4.42 (s, 3H), 3.72 (s,3H). 158

526(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.36 (s, 1H), 8.81 (d, J = 1.8,1H), 8.50 (d, J = 2.3, 1H), 8.18 (d, J = 8.4, 1H), 8.15 (s, 1H), 8.08(d, J = 2.3, 1H), 8.01- 7.97 (m, 1H), 7.77 (td, J = 8.6, 6.4, 1H),7.58-7.53 (m, 1H), 7.20 (td, J = 8.4, 2.3, 1H), 4.29 (m 2H), 3.69 (s,3H), 2.31 (s, 6H). 159

439(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.37 (s, 1H), 8.99 (d, J = 2.0,1H), 8.67-8.55 (m, 3H), 8.42 (d, J = 8.9, 1H), 4.50 (s, 3H), 4.02 (s,3H). 160

512(M + H)+ ¹H NMR (400 MHz, dmso) δ 10.38-10.29 (m, 1H), 8.87 (s, 1H),8.51 (d, J = 2.1, 1H), 8.41 (d, J = 1.6, 1H), 8.10 (d, J = 8.8, 1H),8.02 (d, J = 2.2, 1H), 7.86 (dd, J = 8.9, 1.8, 1H), 7.76 (dd, J = 14.9,8.5, 1H), 7.56 (dd, J = 14.3, 5.5, 1H), 7.20 (t, J = 7.3, 1H), 3.89 (s,3H), 3.66 (m, 3H), 3.52 (s, 3H). 161

469 (M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.46-10.31 (m, 1H), 10.22 (s,1H), 9.38 (s, 1H), 8.82 (d, J = 1.9, 1H), 8.59 (d, J = 2.3, 1H), 8.16(dd, J = 5.4, 3.1, 2H), 8.00 (dd, J = 8.5, 1.9, 1H), 7.77-7.69 (m, 1H),7.59-7.51 (m, 1H), 7.23-7.14 (m, 1H), 3.63 (s, 3H). 162

509 (M + H)⁺ ¹H NMR (400 MHz, dmso) δ 13.11 (s, 1H), 10.60-10.24 (m,1H), 8.83 (d, J = 2.0, 1H), 8.80 (s, 1H), 8.36 (d, J = 2.1, 1H), 7.92(d, J = 8.4, 1H), 7.87 (d, J= 2.3, 1H), 7.82- 7.76 (m, 2H), 7.53 (dd, J= 14.3, 5.4, 1H), 7.20 (td, J = 8.3, 2.0, 1H), 3.68 (s, 3H). 163

485 (M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.50-10.35 (m, 1H), 9.26 (d, J =4.8, 1H), 8.87 (d, J = 1.8, 1H), 8.51 (d, J = 2.3, 1H), 8.16 (d, J =8.4, 1H), 8.07 (d, J = 2.4, 1H), 8.01-7.99 (m, 1H), 7.74 (dt, J = 4.1,1.9, 1H), 7.53 (dd, J = 14.4, 5.3, 1H), 7.22-7.17 (m, 1H), 3.68 (s, 3H),1.30 (dt, J = 8.0, 2.9, 2H), 1.20 (dt, J = 11.4, 5.6, 3H). 164

399(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.44 (s, 1H), 9.27 (s, 1H), 8.53(d, J = 2.2, 1H), 8.40 (s, 1H), 8.16 (d, J = 8.4, 1H), 8.06 (d, J = 2.2,1H), 7.97 (dd, J = 8.5, 1.5, 1H), 4.00 (s, 3H), 3.18-3.13 (m, 2H), 1.27(t, J = 7.3, 3H), 1.20 (s, 3H). 165

482(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.39 (s, 1H), 8.21 (d, J = 8.5,3H), 7.95 (d, J = 6.7, 3H), 3.89 (s, 3H), 3.17 (s, 2H), 2.50 (s, 6H).166

453(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.26 (s, 1H), 8.80 (d, J = 2.1,1H), 8.60 (d, J = 2.2, 1H), 8.56 (d, J = 8.9, 1H), 8.35 (d, J = 8.9,1H), 4.48 (s, 3H), 3.97 (s, 3H), 2.70 (s, 3H). 167

494(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.49 (d, J = 9.7, 1H), 8.57 (d, J =1.8, 1H), 8.45 (d, J = 2.3, 1H), 8.23 (d, J = 8.5, 1H), 8.10 (dd, J =8.5, 1.9, 1H), 8.00 (d, J = 2.3, 1H), 4.01 (s, 3H), 3.71 (dt, J = 18.0,6.8, 4H), 2.89-2.77 (m, 1H), 2.03-1.79 (m, 5H), 1.03-0.92 (m, 4H). 168

468(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.48 (d, J = 2.7, 1H), 8.42 (d, J =2.3, 1H), 8.27 (d, J = 1.8, 1H), 8.25 (d, J = 8.5, 1H), 8.09 (dd, J =8.5, 1.9, 1H), 7.98 (d, J = 2.3, 1H), 4.01 (s, 3H), 3.26 (s, 3H), 3.13(s, 3H), 2.80 (s, 1H), 1.04-0.93 (m, 4H). 169

(M + H)⁺ 1H NMR (400 MHz, dmso) δ 10.13 (s, 1H), 9.49 (s, 1H), 8.37 (d,J = 2.2, 1H), 8.28-8.21 (m, 2H), 8.04 (dd, J = 8.5, 1.8, 1H), 7.95 (d, J= 2.2, 1H), 7.89- 7.81 (m, 2H), 7.63 (t, J = 7.3, 1H), 7.56 (t, J = 7.4,2H), 3.72 (s, 3H), 3.30 (s, 3H), 3.17 (s, 3H). 170

441(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.51 (s, 1H), 9.41 (s, 1H), 8.52(t, J = 2.3, 2H), 8.23 (d, J = 8.4, 1H), 8.10 (d, J = 2.3, 1H), 8.06(dd, J = 8.4, 1.9, 1H), 5.33 (s, 2H), 4.02 (s, 3H), 3.43 (s, 3H), 2.80(m, 1H), 1.06-0.91 (m, 4H). 171

484(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.29 (s, 1H), 8.53 (d, J = 2.3,1H), 8.39 (d, J = 1.6, 1H), 8.17 (d, J = 8.4, 1H), 8.06 (d, J = 2.3,1H), 8.00 (dd, J = 8.4, 1.7, 1H), 3.98 (s, 3H), 3.79-3.74 (m, 2H),3.57-3.53 (m, 4H), 3.08 (s, 3H), 2.96- 2.91 (m, 2H), 2.48 (m 4H). 172

470(M + H)⁺ 1H NMR (400 MHz, dmso) δ 9.33 (s, 1H), 8.84 (d, J = 1.8,1H), 8.51 (d, J = 2.3, 1H), 8.17 (d, J = 8.4, 1H), 8.03 (dd, J = 6.9,2.1, 2H), 4.34 (s, 2H), 3.98 (s, 3H), 3.50 (s, 4H), 3.06 (s, 3H), 2.52(m, 4H). 173

468(M + H)⁺ 1H NMR (400 MHz, dmso) δ 10.44 (s, 1H), 9.18 (s, 1H), 9.06(s, 1H), 8.81 (s, 1H), 8.66 (s, 1H), 8.32-8.17 (m, 2H), 8.06-7.91 (m,2H), 7.83 (s, 1H), 7.64 (s, 1H), 7.27 (s, 1H), 3.72 (s, 3H). 174

454(M + H)⁺ 1H NMR (400 MHz, cd3od) δ 9.23 (s, 1H), 9.00 (s, 1H), 8.37(d, J = 2.1 Hz, 1H), 8.23- 8.18 (m, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.96(d, J = 8.5 Hz, 1H), 4.46 (s, 2H), 4.11 (s, 3H), 3.05 (s, 3H), 2.74 (m,4H), 1.88 (m, 4H). 175

516(M + H)⁺ ¹H NMR (400 MHz, cd3od) δ 9.20 (s, 1H), 8.88 (s, 1H), 8.15(d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J = 6.5 Hz, 3H), 7.78 (d, J= 9.3 Hz, 1H), 7.49-7.39 (m, 3H), 4.45 (m 2H), 3.88 (s, 3H), 2.70 (m,4H), 1.83 (m, 4H). 176

424(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.13 (s, 1H), 9.00 (s, 1H), 8.75(d, J = 1.8, 1H), 8.61 (s, 1H), 8.17-8.14 (m, 2H), 7.97- 7.94 (m, 1H),7.92- 7.90 (m, 1H), 3.98 (s, 3H). 177

484(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.22 (s, 1H), 8.89 (d, J = 2.2,1H), 8.54 (dd, J = 5.5, 3.3, 2H), 8.50 (s, 1H), 8.32 (d, J = 8.9, 1H),5.04 (t, J = 5.9, 2H), 4.00 (s, 3H), 3.45-3.42 (m, 4H), 3.09 (s, 3H),2.90 (t, J = 6.0, 2H), 2.38 (m 4H). 178

496(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 9.22 (s, 1H), 8.52 (d, J = 8.9,1H), 8.47 (dd, J = 4.8, 1.6, 3H), 8.24 (d, J = 8.9, 2H), 5.11-5.05 (m,2H), 3.87 (s, 3H), 2.94-2.90 (m, 2H), 2.14 (s, 6H).

EXAMPLE 11 Synthesis of Compounds 179-182 Compound 179N-(2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)pyridin-3-yl)-4-methylbenzenesulfonamide

A mixture of 7-bromo-2-hydrazinylquinoxaline (1 g, 4.18 mmol) in aceticacid (10 mL) was refluxed for 18 h. Half of the acetic acid was removedunder vacuum and the residue was poured into ice-water. The precipitatewas collected on a filter, washed with water, and dried under vacuo toafford crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as adark red solid (1 g, yield 90%) which was used in the next step withoutfurther purification. MS (m/z): 263 (M+H)⁺.

A mixture of crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline(809 mg, 3.07 mmol), PdCl₂(dppf)₂ (132.6 mg, 0.153 mmol),2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(1 g, 4.3 mmol) and K₂CO₃ (1.7 g, 12.28 mmol) in DMF (40 mL) and water(15 mL) was stirred at 100° C. overnight. Half of solvent was removed.After cooling to room temperature, the resulting mixture was poured intoice-water. The precipitate was collected, washed with water three times,and dried in vacuo to afford crude2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)pyridin-3-amineas grey solid (730 mg, yield 77%) which was used in next step withoutfurther purification. MS (m/z): 307 (M+H)⁺.

To a mixture of crude2-methoxy-5-(1-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)pyridin-3-amine(50 mg, 0.163 mmol) in pyridine (2 mL) was added4-methylbenzene-1-sulfonyl chloride (31.3 mg, 0.164 mmol). The mixturewas stirred at room temperature overnight, and was then heated at 50° C.for 5 h. The solvent was removed, and the residue was purified by PTLCto afford compound 179 as a grey solid (22 mg). ¹H NMR (400 MHz, dmso) δ10.00 (s, 1H), 9.27 (s, 1H), 8.44 (d, J=2.3, 1H), 8.32 (d, J=1.8, 1H),8.15 (d, J=8.4, 1H), 7.98 (d, J=2.3, 1H), 7.89 (dd, J=8.4, 1.8, 1H),7.68 (dd, J=8.4, 1.8, 2H), 7.35 (d, J=8.0, 2H), 3.71 (s, 3H), 3.17 (s,3H), 2.33 (s, 3H). MS (m/z): 461 (M+H)⁺.

The following compounds 180-182 were prepared according to theprocedures for Compound 179 by using the corresponding intermediates andboronic acid or ester under appropriate conditions that could berecognized by one skilled in the art.

Compound Structure LC/MS NMR 180

465(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.31 (s, 1H), 9.28 (s, 1H), 8.51(d, J = 2.0, 1H), 8.36 (s, 1H), 8.16 (d, J = 8.4, 1H), 8.04 (d, J = 2.2,1H), 7.93 (d, J = 8.5, 1H), 7.72 (t, J = 7.5, 2H), 7.48-7.39 (m, 1H),7.31 (t, J = 7.6, 1H), 3.66 (s, 3H), 3.18 (s, 3H). 181

447(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.09 (s, 1H), 9.28 (s, 1H), 8.47(d, J = 2.3, 1H), 8.34 (d, J = 1.8, 1H), 8.16 (d, J = 8.4, 1H), 8.00 (d,J = 2.3, 1H), 7.91 (dd, J = 8.4, 1.8, 1H), 7.79-7.77 (m, 2H), 7.65-7.61(m, 1H), 7.57-7.54 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H). 182

465(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 10.14 (s, 1H), 9.28 (s, 1H), 8.49(d, J = 2.0, 1H), 8.34 (s, 1H), 8.16 (d, J = 8.4, 1H), 8.02 (d, J = 2.0,1H), 7.92 (d, J = 8.5, 1H), 7.83 (dd, J = 8.6, 5.1, 2H), 7.40 (t, J =8.8, 2H), 3.69 (s, 3H), 3.18 (s, 3H).

EXAMPLE 12 Synthesis of Compounds 183 and 184 Compound 1832-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-1-yl)phenyl)-2-methylpropanenitrile

To a white suspension of 1-(2-aminophenyl)ethanone (25 g, 185 mmol) andEt₃N (33.4 mL, 240 mmol) in DCM at 0° C. was added dropwise AcCl (15.70mL, 222 mmol) in 25 mL DCM. The reaction mixture was then stirred atr.t. for 2 h. After the reaction went to completion as monitored byLC-MS, the reaction mixture was cooled to 0° C., and was then quenchedwith H₂O (100 mL). The organic phase was isolated; the aqueous layer wasextracted with DCM. The organic phases were combined, and washed withH₂O and brine. The resulting organic phase was dried over anhydrousMgSO₄, filtered and concentrated to dryness to give crudeN-(2-acetylphenyl)acetamide, which was used in the next step withoutfurther purification (30 g, yield 92%). MS (m/z): 136 (M+H)⁺.

Under N₂, a pale yellow suspension of crude N-(2-acetylphenyl)acetamide(28 g, 158 mmol) in AcOH (300 mL) was stirred for about 5 min, and Br₂(12.95 mL, 253 mmol) was added within 1 h at room temperature. Theresulting mixture was then stirred at room temperature for 75 min. Afterthe reaction went to completion as monitored by LC-MS, the reactionmixture was quenched with H₂O (200 mL). The mixture was filtered throughBuchner funnel, and the solid was collected asN-(2-acetyl-4-bromophenyl)acetamide (35 g, yield 86%). MS (m/z): 216(M+H)⁺.

Under N₂, a mixture of N-(2-acetyl-4-bromophenyl)acetamide (35 g, 137mmol) and HCl (100 mL, 600 mmol) in THF (400 mL) was heated to refluxfor 1 h. After being concentrated under vacuum to remove the solvent,the mixture was treated with EtOAc (100 mL). The aqueous layer wasconcentrated to remove THF, and 6N HCl (100 mL, 600 mmol) was added atroom temperature. After cooling to 0° C., the resulting mixture wastreated dropwise with NaNO₂ (9.43 g, 137 mmol) in 20 mL H₂O. Thereaction mixture was then stirred at r.t. for 15 h. Then the resultingmixture was heated to reflux for another 6 h. The mixture was cooled tor.t. The solid was collected and dried in vacuo, to afford the desiredproduct as a white solid. The crude product was used directly in nextstep without further purification. (19.5 g, yield 63.4%) MS (m/z): 227(M+H)⁺.

Under N₂, an orange solution of 6-bromocinnolin-4-ol (18.5 g, 82 mmol)in HNO₃ (90 mL, 82 mmol) was cooled to 0° C., and H₂SO₄ (30 mL) wasadded. The resulting mixture was then heated at 60° C. for 3 h. Afterthe reaction went to completion as monitored by LC-MS, the reactionmixture was cooled to 0° C., and was then quenched with H₂O (20 mL). Themixture was diluted with EtOAc (25 mL). Following general workupprocedures, the crude residue was added to silica gel, and eluted withPE/EtOAc to give 6-bromo-3-nitrocinnolin-4-ol as a pale yellow solid (13g, yield 58.6%).

Under N₂, a brown solution of 6-bromo-3-nitrocinnolin-4-ol (2 g, 7.41mmol) in DMF (10 mL) was cooled to 0° C., and POCl₃ (0.897 mL, 9.63mmol) was added dropwise. The reaction mixture was stirred at r.t. for 5h. After the reaction went to completion as monitored by LC-MS, thereaction mixture was cooled to 0° C., and then quenched with H₂O (50mL). The mixture was filtered through a Buchner funnel, and the solidwas collected. The crude 6-bromo-4-chloro-3-nitrocinnoline was used inthe next step without further purification (1.75 g, yield 82%). MS(m/z): 290 (M+H)⁺.

A yellow suspension of 6-bromo-4-chloro-3-nitrocinnoline (1.75 g, 6.07mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (1.069 g, 6.67 mmol) andK₂CO₃ (1.677 g, 12.13 mmol) in MeCN (2 mL) was heated to reflux for 5min. The workup followed general workup procedures, and the crude waspurified on silica gel with PE/EtOAc as eluant to give2-(4-(6-bromo-3-nitrocinnolin-4-ylamino)phenyl)-2-methylpropanenitrileas yellow solid (2.5 g, yield 100%). MS (m/z): 414 (M+H)⁺.

Under N₂, an orange solution of2-(4-(6-bromo-3-nitrocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile(2.5 g, 6.06 mmol) and SnCl₂.2H₂O (5.21 g, 24.26 mmol) in EtOAc (50 mL)was heated at 45° C. for 3 h. After cooling to r.t., the pH of themixture was adjusted to 8 with saturated Na₂CO₃. The mixture wasfiltered through a Buchner funnel, and the filtrate was collected andconcentrated to give2-(4-(3-amino-6-bromocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile(1.6 g, yield 69%). MS (m/z): 384 (M+H)⁺.

Under N₂, a brown solution of2-(4-(3-amino-6-bromocinnolin-4-ylamino)phenyl)-2-methyl-propanenitrile(250 mg, 0.654 mmol) in HCO₂H (3 mL) was heated to reflux for 4 h. Thereaction mixture was quenched with H₂O, and was then concentrated toremove the solvent. The crude product was used in the next step directlywithout further purification (250 mg, yield 97%). MS (m/z): 394 (M+H)⁺.

Under N₂, an orange suspension of2-(4-(8-bromo-1H-imidazo[4,5-c]cinnolin-1-yl)phenyl)-2-methylpropanenitrile(100 mg, 0.255 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine(95 mg, 0.331 mmol), Na₂CO₃ (54.0 mg, 0.510 mmol) and PdCl₂(dppf).CH₂Cl₂(10.41 mg, 0.013 mmol) in dioxane (20 mL) and H₂O (2 mL) was stirred for10 minutes at r.t. The resulting mixture was then heated at 120° C. for2 h. The mixture was concentrated in vacuo, and the residue was thenpurified by chromatography to give compound 183 as a pale yellow powder(50 mg). ¹H NMR (400 MHz, dmso) δ 8.87 (s, 1H), 8.63 (d, J=8.9, 1H),8.48 (d, J=2.0, 1H), 8.22 (dd, J=9.0, 1.9, 1H), 7.95 (d, J=8.6, 2H),7.88 (d, J=8.6, 2H), 7.76 (d, J=2.1, 1H), 7.52 (d, J=1.8, 1H), 6.84 (5,2H), 1.78 (5, 6H). MS (m/z): 474 (M+H)+.

The following compound 184 was prepared according to the procedures ofCompound 183 by using the corresponding intermediates and boronic acidor ester under appropriate conditions that could be recognized by oneskilled in the art.

Compound Structure LC/MS NMR 184

488(M + H)⁺ ¹H NMR (400 MHz, dmso) δ 8.56 (d, J = 8.9, 1H), 8.33 (d, J =2.1, 1H), 8.13 (dd, J = 9.0, 2.0, 1H), 7.88 (d, J = 9.3, 4H), 7.69 (d, J= 1.9, 1H), 7.10 (d, J = 1.7, 1H), 6.80 (s, 2H), 2.51 (s, 3H), 1.79 (s,6H).

EXAMPLE 13 PI3Ka Transcreener ADP Assay

Fluorescence polarization was used in this assay. The final conditionsfor kinase assay are 10 μM of ATP, 0.2 ng/μL of PI3Kα kinase, 30 μmol/Lof lipid substrate and assay buffer (50 mmol/L of HEPES (pH 7.5), 100mmol/L of NaCl, 1 mmol/L of EGTA, 3 mmol/L of MgCl₂, 1 mmol/L of DTT and0.03% CHAPS and 2% DMSO).

5 μL of test compounds in 10% DMSO and 10 μL of 0.5 ng/μL PI3K kinase(Invitrogen, PV4788) in assay buffer are put into a 96-well plate(Greiner, Cat. 675076), and then the reaction is started by the additionof 10 μL of 75 μmol/L PIP2, (PS Lipid Substrate Invitrogen, PV5100), and25 μmol/L ATP mixture. After the mixture is incubated for 60 minutes atroom temperature, 25 μL of transcreener Kinase Kit reagent—ADP DetectionMix—(Bellbrook Labs) is added, and the reaction is continued for anadditional 1.5 hours. At the end, the plate is read in a Tecan InfiniteF500 at excitation of 610 nm and emission of 670 nm.

A standard curve for ADP is obtained in a parallel way by replacingcompound and PI3Kα kinase with DMSO and assay buffer, respectively.Different concentration of ADP, 0-10 μM, and ATP, 10-0 μM (ATP+ADP equalto 10 μM) are applied instead of a fixed concentration of ATP in thisstandard curve assay. Other conditions are the same as described above.The standard curve is plotted using Origin 8.0 software. The inhibitionof test compound on ADP production is calculated based on ADPconcentration from standard curve. IC50 is obtained using XLfit 2.0software.

Results

Above compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 20, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 33, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 90, 92, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 142, 143, 144, 145, 147,148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175,176, 177, 178, 179, 180, 181, 182, 183, 184 inhibited the PI3Kα kinasereceptor with IC₅₀<100 nM.

EXAMPLE 14 P-Akt Acumen Assay

Compounds are tested using p-Akt Acumen cell-based assay. The humanprostate cancer cell line PC3 (ATCC) is cultured in F-12 medium with 10%fetal bovine serum. For p-Akt Acumen assay, PC3 cells are seeded at adensity of 5000 cells/90 μL in Poly-D-Lysine 96-well plate (BD, 356692).After incubation for 24 hours, different concentrations of testcompounds (10 μL) is added and cells are incubated for another 2 hours.100 μL of 4% prewarmed paraformaldehyde is added, and cells are fixedfor 45 min at room temperature. After the removal of paraformaldehyde,100 μL of 0.1% Triton X-100 is added, and cells are incubated for extra30 min at room temperature. After the cells are washed twice with 160 μLof PBS, 100 μL of blocking buffer (1% BSA, in PBS) is added, and thecells are continued to incubate for 2˜3 hours. Cells are washed with 160μL of PBS again, treated with 30 μL of Ser473-p-Akt (Cell signaling,CAT: 4060) which is diluted in 0.1% BSA at 1:250, and incubated at 4° C.overnight. Cells are then washed twice with 160 μL of PBS. 35 μL ofAlexa Fluor 488 goat anti-rabbit IgG (Invitrogen, A11034), in a 1:1000dilution buffer (0.1% BSA in PBS), is added, and the reaction mixture isincubated for 1.5 hours in the dark. It is washed twice with 160 μL ofPBS, and then 35 μL of 1.5 μM propidium iodide (Sigma, P4170) is addedto each well, and reaction plate is incubated at 37° C., 5% CO₂ for 30min. Finally, the plate is loaded into the Acumen eX3 (TTP LabTech) andscanned with the appropriate instrument settings.

The inhibition of test compound is calculated based on the ratio ofcompound treated and untreated cells. IC₅₀ is generated using XLfit 2.0software. Each compound specifically exemplified in the inventioninhibited the PI3Kα kinase receptor with IC₅₀<1.0 μM.

EXAMPLE 15 mTOR TR-FRET Assay

Compounds are tested using LanthaScreen TR-FRET Assay. The kinasereaction is completed in 384-well black plate (Corning, Cat. 3676). Thefinal conditions for kinase assay are: 10 μmol/L of ATP, 0.2 ng/μL ofmTOR kinase, 0.4 μmol/L of GFP-4EBP1 substrate and assay buffer (50mmol/L of HEPES, pH 7.5, 0.01% of Tween 20, 1 mmol/L of EGTA, 10 mmol/Lof MnCl₂, 2 mmol/L of DTT and 1% DMSO).

To each well, 2.5 μL of test compounds in 4% DMSO and 2.5 μL of 0.8ng/μL mTOR kinase (Invitrogen, PV4753) diluted in assay buffer areadded. The reaction is initiated by the addition of 5 μL mixture of 0.8μmol/L GFP-4EBP1 Substrate (Invitorgen, PV4759) and 20 μmol/L ATPmixtures. The mixture is incubated at room temperature for 60 minutes.10 μL of 20 mmol/L EDTA and 4 nmol/L Tb-anti-p4EBP1 [pThr46] antibody(Invitrogen, PV4755) diluted in TR-FRET dilution buffer are added andincubated for an additional 1 hour. The plate is then read in a BioTekSynergy2 Reader at excitation of 340 nm and emission of 490 nm and 528nm.

The inhibition of test compound is calculated based on the ratio of 528nm/490 nm. IC₅₀ of test compound is obtained using XLfit 2.0 software.

Results: Above compounds 1, 6, 7, 9, 10, 12, 14, 16, 17, 21, 25, 26, 30,33, 35, 42, 43, 44, 45, 46, 49, 50, 52, 53, 55, 56, 58, 63, 66, 72, 75,88, 96, 98, 102, 103, 105, 106, 107, 119, 120, 121, 122, 123, 129, 131,147, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165,166, 178, 180, 181 inhibited mTOR with IC₅₀<100 nM.

EXAMPLE 16 P-S6 Acumen Assay

Compounds are tested using p-Akt Acumen cell-based assay. The humanprostate cancer cell line PC3 (ATCC) is cultured in F-12 medium with 10%fetal bovine serum. For p-S6 Acumen assay, PC3 cells are seeded atdensity of 5000 cells/90 μL in Poly-D-Lysine 96-well plate (BD, 356692).After incubation for 24 hours, 10 μL of different concentration of testcompounds is added and cells are incubated for 2 hours, followed by theaddition of 100 μL of 4% pre-warmed paraformaldehyde. The cells arefixed at room temperature for 45 min. After removal of theparaformaldehyde solution, 100 μL of 0.1% Triton X-100 is added, andcells are incubated at room temperature for 30 min. After the cells arewashed twice with 160 μL of PBS, 100 μL of blocking buffer (1% BSA, inPBS) is added, and the cells are incubated for an additional 2˜3 hours.Again, cells are washed with 160 μL of PBS, treated with 30 μL of p-S6antibody (Cell signaling, CAT: 4858) which is diluted in 0.1% BSA at1:250, and incubated at 4° C. overnight. After the cells are washedtwice with 160 μL of PBS, 35 μL of Alexa Fluor 488 goat anti-rabbit IgG(Invitrogen, A11034), in a 1:1000 dilution buffer (0.1% BSA in PBS) isadded and the reaction mixture is incubated in the dark for 1.5 hours.After washing twice with 160 μL of PBS, 35 μL of 1.5 μM propidium iodide(Sigma, P4170) is added to each well and reaction plate is incubated at37° C., 5% CO₂ for 30 min. Finally, the plate is loaded into the AcumeneX3 (TTP LabTech) and scanned with the appropriate instrument settings.

The inhibition of the test compound is calculated based on the ratio ofcompound treated and untreated cells. IC₅₀ is generated using XLfit 2.0software. Each compound specifically exemplified in the inventioninhibited mTOR with IC₅₀<10.0 μM.

1. A compound of formula 1:

and/or at least one pharmaceutically acceptable salt thereof wherein A¹is N or CH; A⁴ and A⁵ are independently N or CR²; A² and A³, togetherwith B ring, are a 5-membered heteroaryl or heterocycle containing 1 to4 heteroatoms selected from N, O and S, and said 5-membered heteroarylor heterocycle is optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, —OR^(b),—S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, andheterocycle; provided that A² and A³, together with the B ring, are not

is a single bond or a double bond; R¹ is heteroaryl, optionallysubstituted by one or more groups independently chosen from alkyl,alkenyl, alkynyl, aryl, cycloalkyl, oxo, —C(O)R^(a), —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, haloalkyl,heteroaryl, and heterocycle; R and R² are independently chosen from H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, —C(O)R^(a), —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, haloalkyl, heteroaryl, and heterocycle; andeach of said above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl,heteroaryl and heterocycle can be optionally substituted by one or moregroups independently chosen from optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle; R^(a),R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) are each independentlychosen from H, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl optionally substituted aryl,optionally substituted cycloalkyl, optionally substituted haloalkyl,optionally substituted heteroaryl, and optionally substitutedheterocycle, or R^(a) and R^(c), and/or R^(c) and R^(d), and/or R^(c)and R^(e), and/or R^(c) and R^(f), and/or R^(d) and R^(e), and/or R^(g)and R^(f) together with the atom(s) to which they are attached, form a3-10 membered optionally substituted heterocycle ring; and for eachoccurrence, n is independently 0, 1, or
 2. 2. The compound according toclaim 1, wherein A² and A³, together with B ring, are selected fromstructures (2)-(6)

wherein, t is 1, 2 or 3; and R³ is independently chosen from H,C₁-C₆alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₆-C₁₄aryl, C₃-C₉ memberedcycloalkyl, —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, —OR^(b), —OC(O)R^(a),—OC(O)NR^(c)R^(d), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo,haloalkyl, heteroaryl, and heterocycle; and each of said above alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl and heterocycle can beoptionally substituted by one or more groups independently chosen fromoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle; provided that, when A² and A³, together with Bring, are structure (4), A⁴ is not CR².
 3. The compound according toclaim 2, wherein said R³ is chosen from H, OH, CN, NO₂, halo, C₁-C₆alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₃-C₉ cycloalkyl, heteroaryl,and heterocycle, wherein each of the alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heteroaryl, and heterocycle is optionally substituted by oneor more groups independently chosen from optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted cycloalkyl, —OH,oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d), —NR^(c)R^(d),—NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e), —NR^(c)S(O)_(n)NR^(f)R^(g),—NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e), —NO₂, OR^(b), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d), halo, optionally substituted haloalkyl, optionallysubstituted heteroaryl, and optionally substituted heterocycle.
 4. Thecompound according to claim 2, wherein A² and A³, together with B ring,are chosen from the following structures (2)-(5)


5. The compound according to claim 2, wherein A² and A³, together withthe B ring, are chosen from structures (3)-(4)


6. The compound according to claim 1, wherein A⁴ is N or CH.
 7. Thecompound according to claim 1, wherein A⁵ is N or CH.
 8. The compoundaccording to claim 1, wherein A¹, A⁴, and A⁵ are CH.
 9. The compoundaccording to claim 1, wherein A¹ and A⁵ are CH, and A⁴ is N.
 10. Thecompound according to claim 1, wherein R¹ is a heteroaryl chosen fromthe following structures

wherein each of which is optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,haloalkyl, heteroaryl, heterocycle, oxo, —C(O)R^(a), —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d) and halo, and wherein each of the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl and heterocycle isoptionally substituted by one or more groups independently chosen fromoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle; wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f) and R^(g) are each independently chosen from H, alkyl, aryl,cycloalkyl, haloalkyl, heteroaryl, and heterocycle, further wherein eachof the alkyl, aryl, cycloalkyl, heteroaryl, and heterocycle in R^(a),R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) is optionally substituted byone or more substitutents independently selected from halo and alkyl.11. The compound according to claim 10, wherein R¹ is a heteroarylchosen from

wherein each of which is optionally substituted by one or more groupsindependently chosen from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,haloalkyl, heteroaryl, heterocycle, oxo, —C(O)R^(a), —C(O)OR^(b), —CN,—C(O)NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, —OR^(b), —OC(O)R^(a), —OC(O)NR^(c)R^(d), —S(O)_(n)R^(e),—S(O)_(n)NR^(c)R^(d) and halo, and wherein each of the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl and heterocycle isoptionally substituted by one or more groups independently chosen fromoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle; wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f) and R^(g) are each independently chosen from H, alkyl, aryl,cycloalkyl, haloalkyl, heteroaryl, and heterocycle, further wherein eachof the alkyl, aryl, cycloalkyl, heteroaryl, and heterocycle in R^(a),R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) is optionally substituted byone or more substitutents independently selected from halo and alkyl.12. The compound according to claim 1, wherein R¹ is

which is optionally substituted with one or more groups independentlychosen from: alkyl, alkenyl, alkynyl, wherein each of which isoptionally substituted by one or more groups independently chosen fromoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, —OH, oxo, —C(O)R^(a), —C(O)OR^(b), —CN, —C(O)NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(a), —NR^(c)S(O)_(n)R^(e),—NR^(c)S(O)_(n)NR^(f)R^(g), —NR^(c)C(O)OR^(b), —NR^(c)C(O)NR^(d)R^(e),—NO₂, OR^(b), —S(O)_(n)R^(e), —S(O)_(n)NR^(c)R^(d), halo, optionallysubstituted haloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocycle; C(O)NR^(c)R^(d); NR^(c)R^(d); OR^(b); halo;cyano; NR^(c)S(O)_(n)R^(e), wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f) and R^(g) are each independently chosen from H, alkyl, aryl,cycloalkyl, haloalkyl, heteroaryl, and heterocycle, wherein each of thealkyl, aryl, cycloalkyl, heteroaryl, and heterocycle in R^(a), R^(b),R^(c), R^(d), R^(e), R^(f) and R^(g) is optionally substituted by one ormore substitutents independently selected from halo and alkyl.
 13. Acompound selected from compounds 1 to 184 and/or at least onepharmaceutically acceptable salt.
 14. A pharmaceutical compositioncomprising at least one compound and/or at least one pharmaceuticallyacceptable salt thereof according to claim 1 and at least onepharmaceutically acceptable carrier.
 15. A method of inhibiting theactivity of PI3K and/or mTOR comprising contacting the enzyme with aneffective amount of at least one compound and/or at least onepharmaceutically acceptable salt thereof according to claim
 1. 16. Amethod of treating cancer responsive to inhibition of PI3K and/or mTORcomprising administering to a subject in need thereof an effectiveamount of at least one compound and/or at least one pharmaceuticallyacceptable salt thereof according to claim
 1. 17. (canceled) 18.(canceled)